2-227256385-G-T

Variant names:

• chr2-227256385-G-T
• rs55703767
• NM_000091.5:c.976G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.976G>T​(p.Asp326Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,610,916 control chromosomes in the GnomAD database, including 31,711 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D326D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2278 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29433 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.554
• Publications: 67 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 -18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.006026387).
• BP6: Variant 2-227256385-G-T is Benign according to our data. Variant chr2-227256385-G-T is described in ClinVar as Benign. ClinVar VariationId is 255010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

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.976G>T	p.Asp326Tyr	missense	Exon 17 of 52	NP_000082.2
	MFF-DT	NR_102371.1		n.1592+2793C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.976G>T	p.Asp326Tyr	missense	Exon 17 of 52	ENSP00000379823.3
	MFF-DT	ENST00000439598.6	TSL:1	n.1592+2793C>A		intron	N/A
	MFF-DT	ENST00000396588.6	TSL:2	n.1658+2793C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23466 AN: 152034 Hom.: 2280 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.169 AC: 42103 AN: 249230 AF XY: 0.172

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.195 AC: 284458 AN: 1458764 Hom.: 29433 Cov.: 31 AF XY: 0.194 AC XY: 141088 AN XY: 725836

African (AFR) AF: 0.0328 AC: 1099 AN: 33456

American (AMR) AF: 0.110 AC: 4919 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5843 AN: 26110

East Asian (EAS) AF: 0.124 AC: 4934 AN: 39678

South Asian (SAS) AF: 0.116 AC: 9999 AN: 86198

European-Finnish (FIN) AF: 0.195 AC: 10388 AN: 53358

Middle Eastern (MID) AF: 0.215 AC: 1231 AN: 5728

European-Non Finnish (NFE) AF: 0.212 AC: 234919 AN: 1109222

Other (OTH) AF: 0.184 AC: 11126 AN: 60306

GnomAD4 genome AF: 0.154 AC: 23463 AN: 152152 Hom.: 2278 Cov.: 32 AF XY: 0.152 AC XY: 11315 AN XY: 74374

African (AFR) AF: 0.0398 AC: 1654 AN: 41538

American (AMR) AF: 0.155 AC: 2367 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 810 AN: 3468

East Asian (EAS) AF: 0.118 AC: 611 AN: 5180

South Asian (SAS) AF: 0.117 AC: 565 AN: 4810

European-Finnish (FIN) AF: 0.189 AC: 1994 AN: 10572

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14685 AN: 67988

Other (OTH) AF: 0.188 AC: 396 AN: 2112

Alfa AF: 0.194 Hom.: 6098

Bravo AF: 0.148

TwinsUK AF: 0.206 AC: 764

ALSPAC AF: 0.208 AC: 802

ESP6500AA AF: 0.0429 AC: 159

ESP6500EA AF: 0.221 AC: 1814

ExAC AF: 0.167 AC: 20129

Asia WGS AF: 0.129 AC: 449 AN: 3478

EpiCase AF: 0.235

EpiControl AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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

p.Asp326Tyr in exon 17 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 21.64% (14422/66634) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs55703767).

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.

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 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported.

Apr 22, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alport syndrome Benign:2

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.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.55
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.19
Sift	Benign	0.11	T
Sift4G	Benign	0.067	T
Polyphen		0.29	B
Vest4		0.092
MPC		0.66
ClinPred		0.013	T
GERP RS		3.0
Varity_R		0.20
gMVP		0.36
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs55703767; hg19: chr2-228121101; COSMIC: COSV67412889;