chr2-227263824-C-T

Variant names:

• chr2-227263824-C-T
• rs10205042
• NM_000091.5:c.1195C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000091.5(COL4A3):​c.1195C>T​(p.Leu399Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,613,536 control chromosomes in the GnomAD database, including 456,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L399L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (40860 hom., cov: 32)
  • Exomes 𝑓: 0.75 (415939 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.664
• Publications: 29 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 2-227263824-C-T is Benign according to our data. Variant chr2-227263824-C-T is described in ClinVar as Benign. ClinVar VariationId is 254976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.664 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1195C>T	p.Leu399Leu	synonymous_variant	Exon 21 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1195C>T	p.Leu399Leu	synonymous_variant	Exon 21 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111237 AN: 151988 Hom.: 40817 Cov.: 32

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.878

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.686

GnomAD2 exomes AF: 0.768 AC: 191130 AN: 248780 AF XY: 0.766

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.846

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.884

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.737

Gnomad OTH exome AF: 0.744

GnomAD4 exome AF: 0.753 AC: 1100520 AN: 1461430 Hom.: 415939 Cov.: 48 AF XY: 0.753 AC XY: 547225 AN XY: 727030

African (AFR) AF: 0.667 AC: 22329 AN: 33468

American (AMR) AF: 0.837 AC: 37436 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 16783 AN: 26132

East Asian (EAS) AF: 0.868 AC: 34447 AN: 39690

South Asian (SAS) AF: 0.806 AC: 69531 AN: 86242

European-Finnish (FIN) AF: 0.795 AC: 42430 AN: 53380

Middle Eastern (MID) AF: 0.649 AC: 3744 AN: 5768

European-Non Finnish (NFE) AF: 0.745 AC: 828511 AN: 1111656

Other (OTH) AF: 0.750 AC: 45309 AN: 60380

GnomAD4 genome AF: 0.732 AC: 111337 AN: 152106 Hom.: 40860 Cov.: 32 AF XY: 0.736 AC XY: 54731 AN XY: 74364

African (AFR) AF: 0.673 AC: 27914 AN: 41478

American (AMR) AF: 0.769 AC: 11772 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2215 AN: 3470

East Asian (EAS) AF: 0.878 AC: 4546 AN: 5180

South Asian (SAS) AF: 0.816 AC: 3930 AN: 4814

European-Finnish (FIN) AF: 0.800 AC: 8462 AN: 10574

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.741 AC: 50343 AN: 67972

Other (OTH) AF: 0.685 AC: 1447 AN: 2112

Alfa AF: 0.720 Hom.: 18021

Bravo AF: 0.726

Asia WGS AF: 0.808 AC: 2813 AN: 3478

EpiCase AF: 0.713

EpiControl AF: 0.718

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Apr 22, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Leu399Leu in exon 21 of COL4A3: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 89.00% (7590/8528) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs10205042). -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 92% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 86. Only high quality variants are reported. -

Alport syndrome Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Autosomal recessive Alport syndrome Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Alport syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.9
DANN	Benign	0.76
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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: rs10205042; hg19: chr2-228128540; COSMIC: COSV108247715; COSMIC: COSV108247715;