rs55816283

Variant names:

• chr2-227293305-C-T
• rs55816283
• NM_000091.5:c.3325C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000091.5(COL4A3):​c.3325C>T​(p.Pro1109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,613,784 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign 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. P1109L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (44 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.45

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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0191468).
• BP6: Variant 2-227293305-C-T is Benign according to our data. Variant chr2-227293305-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254993.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=5}. Variant chr2-227293305-C-T is described in Lovd as [Likely_benign]. Variant chr2-227293305-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00414 (631/152296) while in subpopulation NFE AF = 0.00609 (414/68028). AF 95% confidence interval is 0.0056. There are 4 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.3325C>T	p.Pro1109Ser	missense_variant	Exon 38 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.3325C>T	p.Pro1109Ser	missense_variant	Exon 38 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 632 AN: 152178 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00430 AC: 1072 AN: 249366 AF XY: 0.00458

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00278

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00621 AC: 9070 AN: 1461488 Hom.: 44 Cov.: 31 AF XY: 0.00613 AC XY: 4460 AN XY: 727056

Gnomad4 AFR exome AF: 0.000956 AC: 32 AN: 33470

Gnomad4 AMR exome AF: 0.00320 AC: 143 AN: 44714

Gnomad4 ASJ exome AF: 0.0119 AC: 311 AN: 26120

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.00375 AC: 323 AN: 86234

Gnomad4 FIN exome AF: 0.00262 AC: 140 AN: 53408

Gnomad4 NFE exome AF: 0.00699 AC: 7775 AN: 1111958

Gnomad4 Remaining exome AF: 0.00537 AC: 324 AN: 60364

GnomAD4 genome AF: 0.00414 AC: 631 AN: 152296 Hom.: 4 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74462

Gnomad4 AFR AF: 0.00137 AC: 0.00137145 AN: 0.00137145

Gnomad4 AMR AF: 0.00281 AC: 0.00281119 AN: 0.00281119

Gnomad4 ASJ AF: 0.0121 AC: 0.0121037 AN: 0.0121037

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00498 AC: 0.00497512 AN: 0.00497512

Gnomad4 FIN AF: 0.00320 AC: 0.00320211 AN: 0.00320211

Gnomad4 NFE AF: 0.00609 AC: 0.00608573 AN: 0.00608573

Gnomad4 OTH AF: 0.00710 AC: 0.00710227 AN: 0.00710227

Alfa AF: 0.00584 Hom.: 5

Bravo AF: 0.00419

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00108 AC: 4

ESP6500EA AF: 0.00735 AC: 60

ExAC AF: 0.00423 AC: 511

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00699

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro1109Ser in exon 38 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 0.56% (376/66566) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs55816283). -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 08, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A3 c.3325C>T (p.Pro1109Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0042 in 280758 control chromosomes with 7 homozygotes (gnomAD), occuring predominantly at a frequency of 0.0057 within the Non-Finnish European subpopulation in the gnomAD database with 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3325C>T has been reported in the literature in individuals affected with Kidney Disorders (Longo_2002, Wang_2004, Papazachariou_2014, Kovacs_2016), often times reported as a polymorphism due to its heterozygosity index (Wang_2004), high mean allele frequency (Papazachariou_2014), or other variants being causitive of disease (Kovacs_2016). These reports suggest the variant is not likely to be associated with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign. -

Nov 20, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Feb 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 14871398, 12028435, 17216251, 29981437) -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL4A3: BS2 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Alport syndrome Uncertain:1

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Kidney disorder Benign:1

Apr 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL4A3-related disorder Benign:1

Jul 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.75	P;.
Vest4		0.50
MVP		0.87
MPC		0.19
ClinPred		0.012	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.36
Mutation Taster		=91/9	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs55816283; hg19: chr2-228158021; COSMIC: COSV107359216;