rs147085074

chr2-227293238-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000091.5(COL4A3):c.3258G>A(p.Gly1086=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00472 in 1,613,918 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (37 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.953

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-227293238-G-A is Benign according to our data. Variant chr2-227293238-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254991.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=5, Uncertain_significance=1}. Variant chr2-227293238-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.953 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00385 (586/152286) while in subpopulation AMR AF= 0.00654 (100/15300). AF 95% confidence interval is 0.0055. There are 2 homozygotes in gnomad4. There are 304 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.3258G>A	p.Gly1086=	synonymous_variant	38/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.244-11449C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.3258G>A	p.Gly1086=	synonymous_variant	38/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.244-11449C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00444 AC: 1109 AN: 249512 Hom.: 9 AF XY: 0.00454 AC XY: 615 AN XY: 135370

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.0309

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00484

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00726

GnomAD4 exome AF: 0.00481 AC: 7026 AN: 1461632 Hom.: 37 Cov.: 31 AF XY: 0.00478 AC XY: 3476 AN XY: 727118

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.0300

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00461

Gnomad4 OTH exome AF: 0.00701

GnomAD4 genome AF: 0.00385 AC: 586 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.00408 AC XY: 304 AN XY: 74462

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.0302

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00619 Hom.: 4

Bravo AF: 0.00437

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COL4A3: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gly1086Gly in exon 38 of COL4A3: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 0.54% (361/66654) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs147085074). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2018	- -

Alport syndrome Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	4.8
Dann	Benign	0.70

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: rs147085074; hg19: chr2-228157954;