rs121912863

Variant names:

• chr2-227008112-G-A
• rs121912863
• NM_000092.5:c.4715C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_000092.5(COL4A4):​c.4715C>T​(p.Pro1572Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,613,954 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1572P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:9 B:1
• Conservation: PhyloP100: 6.79
• Publications: 14 publications found

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 Gene-Disease associations (from GenCC):

• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000236 (36/152360) while in subpopulation EAS AF = 0.00174 (9/5184). AF 95% confidence interval is 0.000905. There are 1 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4715C>T	p.Pro1572Leu	missense_variant	Exon 47 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4715C>T	p.Pro1572Leu	missense_variant	Exon 47 of 48	5	NM_000092.5	ENSP00000379866.3
COL4A4	ENST00000682098.1	c.317C>T	p.Pro106Leu	missense_variant	Exon 2 of 3			ENSP00000508331.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152242 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 248514 AF XY: 0.000163

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000125 AC: 183 AN: 1461594 Hom.: 1 Cov.: 32 AF XY: 0.000117 AC XY: 85 AN XY: 727086

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.000983 AC: 39 AN: 39694

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111892

Other (OTH) AF: 0.00116 AC: 70 AN: 60374

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152360 Hom.: 1 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74506

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.00131 AC: 20 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000594 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000141 AC: 17

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alport syndrome Pathogenic:2 Uncertain:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with Alport syndrome. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMID: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). Thin basement membrane nephropathy and focal segmental glomerulosclerosis are associated with autosomal dominant inheritance (OMIM, PMID: 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 44 heterozygotes, 0 homozygotes, v3: 35 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated collagen IV NC1 domain (PMID: 25381091, 9792860). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals.This variant has been classified as a VUS several times by diagnostic laboratories in ClinVar, and once as likely benign, but has also been classified as likely pathogenic or pathogenic many times in individuals with Alport syndrome. There is good evidence for the pathogenicity of this variant in autosomal recessive disease, and some evidence for pathogenicity in autosomal dominant disease (ClinVar, LOVD, PMID: 22887978, 25381091, 28976722, 31019026, 31246743, 31589614, 33772369, 9792860, 37097554). Recent literature also reports individuals who are heterozygous for this variant as unaffected carriers, or report other variants that account for their observed phenotype (PMID: 35114279, 36370330, 36349777, 37147621). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been observed in an unaffected parent (PMID: 25381091). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

not provided Uncertain:2 Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second variant in a patient with mesangial proliferative nephropathy in published literature (PMID: 25381091); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31019026, 31589614, 32154576, 22887978, 35114279, 33772369, 36349777, 9792860, 34645491, 37097554, 36130833, 25381091, 39540369, 38972501) -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Mar 01, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A4 c.4715C>T (p.Pro1572Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 248514 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (0.00016 vs 0.0016), allowing no conclusion about variant significance. c.4715C>T has been reported in the literature in individuals affected with Alport Syndrome, Autosomal Recessive. These reports do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive Alport syndrome Pathogenic:1

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Autosomal recessive Alport syndrome;CN376803:Hematuria, benign familial, 1 Uncertain:1

Mar 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kidney disorder Uncertain:1

Jan 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Nov 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4715C>T (p.P1572L) alteration is located in exon 47 (coding exon 46) of the COL4A4 gene. This alteration results from a C to T substitution at nucleotide position 4715, causing the proline (P) at amino acid position 1572 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

COL4A4-related disorder Uncertain:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL4A4 c.4715C>T variant is predicted to result in the amino acid substitution p.Pro1572Leu. This variant has been reported in the heterozygous state in individuals with suspected autosomal recessive Alport syndrome, although a second COL4A4 variant was not detected (Boye et al. 1998. PubMed ID: 9792860; Supplementary Table S1, De La Vega et al. 2021. PubMed ID: 34645491; Zhang et al. 2021. PubMed ID: 33772369). This variant has also been noted as paternally inherited in a compound heterozygote state in a patient with mesangial proliferative nephropathy (Lin et al. 2014. PubMed ID: 25381091) and in a heterozygous state in patients with IgA neuropathy and collagen III glomerulopathy (Liu et al. 2023. PubMed ID: 36370330; Table S5, Table S7, Yuan et al. 2022. PubMed ID: 36130833). This variant was also paternally inherited in an individual with anemia, nephritis, hepatitis, and recurrent gastroenteritis, but a second COL4A4 variant was not detected and phenotype information of the father was not available (Table S2, Table S15, Clark et al. 2019. PubMed ID: 31019026). Digenic inheritance and predisposition factors have been suggested for the combination of this variant with other genes because the variant has been noted in a patient with Alport syndrome who also carried a COL4A5 variant (Supplementary Table 1, Zhou et al. 2023. PubMed ID: 37097554), in a patient with concurrent IgA neuropathy and thin basement membrane nephropathy who also carried NPHS2 and ITGB4 variants (Xu et al. 2022. PubMed ID: 36349777), and a similar COL4A4 variant (p.Pro1569Leu) was noted in a patient who also carried a COL6A1 variant (Supplementary Table 1, Pan et al. 2020. PubMed ID: 32154576). The c.4715C>T variant is reported in 0.14% of alleles in individuals of East Asian descent in gnomAD, suggesting the variant may be too common for autosomal dominant disease. Although we suspect that the c.4715C>T variant may contribute to autosomal recessive COL4A4 disorders, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.87
MPC		0.14
ClinPred		0.47	T
GERP RS		5.7
Varity_R		0.59
gMVP		0.55
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912863; hg19: chr2-227872828; COSMIC: COSV61632576;