rs184730597

Variant names:

• chr2-227240170-G-A
• rs184730597
• NM_000091.5:c.172G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-227240170-G-A
• chr2-227240170-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5 PP3_Strong PP5

The NM_000091.5(COL4A3):​c.172G>A​(p.Gly58Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,611,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G58R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:4
• Conservation: PhyloP100: 4.93
• Publications: 4 publications found

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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. [provided by RefSeq, Jun 2010]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-227240170-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3585962.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 2-227240170-G-A is Pathogenic according to our data. Variant chr2-227240170-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 553693.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	NM_000091.5	MANE Select	c.172G>A	p.Gly58Ser	missense	Exon 3 of 52	NP_000082.2
	MFF-DT	NR_102371.1		n.1593-1996C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.172G>A	p.Gly58Ser	missense	Exon 3 of 52	ENSP00000379823.3
	MFF-DT	ENST00000439598.6	TSL:1	n.1593-1996C>T		intron	N/A
	MFF-DT	ENST00000433324.2	TSL:5	n.4607-1996C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000247 AC: 6 AN: 243384 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000882

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1458968 Hom.: 0 Cov.: 32 AF XY: 0.0000221 AC XY: 16 AN XY: 725390

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.0000900 AC: 4 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39620

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1110864

Other (OTH) AF: 0.0000498 AC: 3 AN: 60264

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74412

African (AFR) AF: 0.00 AC: 0 AN: 41530

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000598 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:2

Mar 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the published literature in an individual with benign familial hematuria (PMID: 24854265); 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: 34426522, 34400539, 28632965, 24854265)

Aug 11, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 58 of the COL4A3 protein (p.Gly58Ser). This variant is present in population databases (rs184730597, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of benign familial hematuria (PMID: 24854265). ClinVar contains an entry for this variant (Variation ID: 553693). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Nov 22, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features of Alport syndrome. The majority of the pathogenic variants in this gene involve the substitution of a glycine residue in the triple-helix domain, resulting in disruption of protein function (PMID: 29632050, 21421911, 19344236). Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.

Hematuria, benign familial, 2;C5882663:Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive Pathogenic:1

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alport syndrome Pathogenic:1

May 25, 2020

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_v1.1.1, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (6 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif (glycine residue of the Gly-X-Y motif in triple helical region; PDB). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as likely pathogenic and a variant of uncertain significance (ClinVar, PMIDs: 28632965, 24854265). It has been reported in a glomerular familial microscopic hematuria (FMH) patient cohort and a hematuric nephropathy patient cohort. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Autosomal dominant Alport syndrome Pathogenic:1

Oct 21, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PP3, PP5

not specified Uncertain:1

Jan 20, 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: COL4A3 c.172G>A (p.Gly58Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) region of 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 2.5e-05 in 243384 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.172G>A has been reported in the literature in at-least one individual affected with benign familial hematuria (example: Moriniere_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Autosomal recessive Alport syndrome Uncertain:1

Sep 12, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		4.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.95
MPC		0.75
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.93
Mutation Taster		=25/75	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: rs184730597; hg19: chr2-228104886; COSMIC: COSV67413256;