rs77431913

Variant names:

• chr2-227254099-G-A
• rs77431913
• NM_000091.5:c.766-13G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-227254099-G-A
• chr2-227254099-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.766-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,612,466 control chromosomes in the GnomAD database, including 915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (197 hom., cov: 32)
  • Exomes 𝑓: 0.010 (718 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.120
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-227254099-G-A is Benign according to our data. Variant chr2-227254099-G-A is described in ClinVar as [Benign]. Clinvar id is 255005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.766-13G>A		intron_variant	Intron 13 of 51	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.766-13G>A		intron_variant	Intron 13 of 51	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4624 AN: 152082 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.0685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0249 AC: 6207 AN: 249190 AF XY: 0.0229

Gnomad AFR exome AF: 0.0703

Gnomad AMR exome AF: 0.00733

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.181

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0105 AC: 15287 AN: 1460266 Hom.: 718 Cov.: 31 AF XY: 0.0104 AC XY: 7565 AN XY: 726550

African (AFR) AF: 0.0709 AC: 2358 AN: 33256

American (AMR) AF: 0.00796 AC: 356 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 124 AN: 26116

East Asian (EAS) AF: 0.168 AC: 6668 AN: 39622

South Asian (SAS) AF: 0.0154 AC: 1325 AN: 86206

European-Finnish (FIN) AF: 0.0252 AC: 1345 AN: 53402

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5750

European-Non Finnish (NFE) AF: 0.00161 AC: 1787 AN: 1110940

Other (OTH) AF: 0.0203 AC: 1226 AN: 60262

GnomAD4 genome AF: 0.0304 AC: 4627 AN: 152200 Hom.: 197 Cov.: 32 AF XY: 0.0318 AC XY: 2365 AN XY: 74392

African (AFR) AF: 0.0685 AC: 2846 AN: 41528

American (AMR) AF: 0.0147 AC: 224 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.170 AC: 878 AN: 5172

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4828

European-Finnish (FIN) AF: 0.0270 AC: 286 AN: 10582

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 68020

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0155 Hom.: 23

Bravo AF: 0.0322

Asia WGS AF: 0.103 AC: 358 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.766-13G>A in intron 13 of COL4A3: This variant is not expected to have clinica l significance because it has been identified in 18.09% (1554/8590) of East Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs77431913). -

Alport syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.9
DANN	Benign	0.47
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.010		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: rs77431913; hg19: chr2-228118815;