rs34019152

Variant names:

• chr2-227267036-G-A
• rs34019152
• NM_000091.5:c.1452G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-227267036-G-A
• chr2-227267036-G-C

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.1452G>A​(p.Gly484Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,612,894 control chromosomes in the GnomAD database, including 5,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (580 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5216 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.356
• Publications: 18 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=-0.81).
• BP6: Variant 2-227267036-G-A is Benign according to our data. Variant chr2-227267036-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.356 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1452G>A	p.Gly484Gly	synonymous_variant	Exon 23 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1452G>A	p.Gly484Gly	synonymous_variant	Exon 23 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 11820 AN: 152014 Hom.: 573 Cov.: 32

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0894

GnomAD2 exomes AF: 0.0957 AC: 23868 AN: 249488 AF XY: 0.0949

Gnomad AFR exome AF: 0.0503

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.0900

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.0761

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0793 AC: 115787 AN: 1460760 Hom.: 5216 Cov.: 31 AF XY: 0.0801 AC XY: 58230 AN XY: 726702

African (AFR) AF: 0.0475 AC: 1588 AN: 33456

American (AMR) AF: 0.176 AC: 7885 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0900 AC: 2350 AN: 26118

East Asian (EAS) AF: 0.122 AC: 4857 AN: 39682

South Asian (SAS) AF: 0.112 AC: 9636 AN: 86218

European-Finnish (FIN) AF: 0.0357 AC: 1909 AN: 53406

Middle Eastern (MID) AF: 0.0998 AC: 575 AN: 5764

European-Non Finnish (NFE) AF: 0.0734 AC: 81504 AN: 1111060

Other (OTH) AF: 0.0909 AC: 5483 AN: 60346

GnomAD4 genome AF: 0.0779 AC: 11849 AN: 152134 Hom.: 580 Cov.: 32 AF XY: 0.0787 AC XY: 5856 AN XY: 74368

African (AFR) AF: 0.0494 AC: 2052 AN: 41518

American (AMR) AF: 0.167 AC: 2549 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3472

East Asian (EAS) AF: 0.152 AC: 787 AN: 5164

South Asian (SAS) AF: 0.106 AC: 510 AN: 4816

European-Finnish (FIN) AF: 0.0313 AC: 331 AN: 10588

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.0734 AC: 4987 AN: 67984

Other (OTH) AF: 0.0960 AC: 203 AN: 2114

Alfa AF: 0.0746 Hom.: 244

Bravo AF: 0.0875

Asia WGS AF: 0.139 AC: 483 AN: 3478

EpiCase AF: 0.0875

EpiControl AF: 0.0901

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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.Gly484Gly in exon 23 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 17.66% (2037/11532 ) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs34019152). -

May 24, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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 28% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 26. Only high quality variants are reported. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Autosomal recessive Alport syndrome Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Benign:1

Dec 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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	-0.81
CADD	Benign	0.94
DANN	Benign	0.48
PhyloP100		0.36
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: rs34019152; hg19: chr2-228131752; COSMIC: COSV101169992; COSMIC: COSV101169992;