rs1800516

chr2-227082177-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):c.1634G>C(p.Gly545Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0318 in 1,613,770 control chromosomes in the GnomAD database, including 899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G545V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.031 (84 hom., cov: 32)
  • Exomes 𝑓: 0.032 (815 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.08

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072841644).
• BP6: Variant 2-227082177-C-G is Benign according to our data. Variant chr2-227082177-C-G is described in ClinVar as [Benign]. Clinvar id is 255015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227082177-C-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.1634G>C	p.Gly545Ala	missense_variant	23/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.1634G>C	p.Gly545Ala	missense_variant	23/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4679 AN: 152136 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0272 AC: 6788 AN: 249500 Hom.: 122 AF XY: 0.0271 AC XY: 3665 AN XY: 135358

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0431

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00788

Gnomad FIN exome AF: 0.0226

Gnomad NFE exome AF: 0.0375

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0319 AC: 46619 AN: 1461516 Hom.: 815 Cov.: 31 AF XY: 0.0316 AC XY: 22982 AN XY: 727118

Gnomad4 AFR exome AF: 0.0359

Gnomad4 AMR exome AF: 0.0196

Gnomad4 ASJ exome AF: 0.0414

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00822

Gnomad4 FIN exome AF: 0.0215

Gnomad4 NFE exome AF: 0.0352

Gnomad4 OTH exome AF: 0.0333

GnomAD4 genome AF: 0.0307 AC: 4678 AN: 152254 Hom.: 84 Cov.: 32 AF XY: 0.0295 AC XY: 2198 AN XY: 74456

Gnomad4 AFR AF: 0.0342

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.0213

Gnomad4 NFE AF: 0.0343

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0344 Hom.: 80

Bravo AF: 0.0315

TwinsUK AF: 0.0410 AC: 152

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.0322 AC: 125

ESP6500EA AF: 0.0358 AC: 296

ExAC AF: 0.0282 AC: 3408

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0359

EpiControl AF: 0.0407

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2017	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. -
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.Gly545Ala in exon 23 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 3.93% (2622/66738) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs1800516). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 14, 2017	- -

Alport syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0073	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.32
MPC		0.64
ClinPred		0.085	T
GERP RS		5.3
Varity_R		0.85
gMVP		0.99

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: rs1800516; hg19: chr2-227946893; COSMIC: COSV61632129;