rs1800517

chr2-227051116-G-Achr2-227051116-G-Cchr2-227051116-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):c.3011C>T(p.Pro1004Leu) variant causes a missense change. The variant allele was found at a frequency of 0.497 in 1,613,426 control chromosomes in the GnomAD database, including 201,002 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. P1004P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.51 (20139 hom., cov: 31)
  • Exomes 𝑓: 0.50 (180863 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.51

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=3.101142E-5).
• BP6: Variant 2-227051116-G-A is Benign according to our data. Variant chr2-227051116-G-A is described in ClinVar as [Benign]. Clinvar id is 255028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227051116-G-A is described in Lovd as [Benign]. Variant chr2-227051116-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.3011C>T	p.Pro1004Leu	missense_variant	33/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.3011C>T	p.Pro1004Leu	missense_variant	33/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77872 AN: 151810 Hom.: 20112 Cov.: 31

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.500

GnomAD3 exomes AF: 0.520 AC: 129808 AN: 249542 Hom.: 34169 AF XY: 0.522 AC XY: 70647 AN XY: 135388

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.453

Gnomad SAS exome AF: 0.641

Gnomad FIN exome AF: 0.507

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.511

GnomAD4 exome AF: 0.495 AC: 723660 AN: 1461498 Hom.: 180863 Cov.: 52 AF XY: 0.498 AC XY: 362087 AN XY: 727070

Gnomad4 AFR exome AF: 0.566

Gnomad4 AMR exome AF: 0.549

Gnomad4 ASJ exome AF: 0.579

Gnomad4 EAS exome AF: 0.466

Gnomad4 SAS exome AF: 0.638

Gnomad4 FIN exome AF: 0.508

Gnomad4 NFE exome AF: 0.478

Gnomad4 OTH exome AF: 0.501

GnomAD4 genome AF: 0.513 AC: 77950 AN: 151928 Hom.: 20139 Cov.: 31 AF XY: 0.514 AC XY: 38160 AN XY: 74226

Gnomad4 AFR AF: 0.566

Gnomad4 AMR AF: 0.514

Gnomad4 ASJ AF: 0.556

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.630

Gnomad4 FIN AF: 0.499

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.500

Alfa AF: 0.482 Hom.: 31765

Bravo AF: 0.515

TwinsUK AF: 0.483 AC: 1790

ALSPAC AF: 0.470 AC: 1811

ESP6500AA AF: 0.582 AC: 2198

ESP6500EA AF: 0.489 AC: 4022

ExAC AF: 0.520 AC: 62858

Asia WGS AF: 0.563 AC: 1959 AN: 3478

EpiCase AF: 0.462

EpiControl AF: 0.476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro1004Leu in exon 33 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 64.34% (10624/16512) of South As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs1800517). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Alport syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, 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 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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.024
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.000031	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	3.1e-9	P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.63	P
Vest4		0.12
MPC		0.14
ClinPred		0.082	T
GERP RS		4.6
Varity_R		0.41
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800517; hg19: chr2-227915832; COSMIC: COSV61632594;