rs80243096

chr2-227052374-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000092.5(COL4A4):c.2899A>G(p.Ile967Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00797 in 1,612,552 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (77 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.247

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=0.0029687583).
• BP6: Variant 2-227052374-T-C is Benign according to our data. Variant chr2-227052374-T-C is described in ClinVar as [Benign]. Clinvar id is 255025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227052374-T-C is described in Lovd as [Benign]. Variant chr2-227052374-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0164 (2490/152288) while in subpopulation AFR AF= 0.0426 (1769/41556). AF 95% confidence interval is 0.0409. There are 30 homozygotes in gnomad4. There are 1159 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.2899A>G	p.Ile967Val	missense_variant	32/48	ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.2899A>G	p.Ile967Val	missense_variant	32/48	5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2487 AN: 152170 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00712 AC: 1777 AN: 249560 Hom.: 19 AF XY: 0.00626 AC XY: 847 AN XY: 135394

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00652

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00642

Gnomad OTH exome AF: 0.00709

GnomAD4 exome AF: 0.00709 AC: 10356 AN: 1460264 Hom.: 77 Cov.: 30 AF XY: 0.00678 AC XY: 4925 AN XY: 726604

Gnomad4 AFR exome AF: 0.0496

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000905

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00690

Gnomad4 OTH exome AF: 0.00792

GnomAD4 genome AF: 0.0164 AC: 2490 AN: 152288 Hom.: 30 Cov.: 32 AF XY: 0.0156 AC XY: 1159 AN XY: 74460

Gnomad4 AFR AF: 0.0426

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00657

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00810 Hom.: 15

Bravo AF: 0.0187

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.0393 AC: 145

ESP6500EA AF: 0.00648 AC: 53

ExAC AF: 0.00730 AC: 882

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00771

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 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.Ile967Val in exon 32 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 4.54% (445/9802) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs80243096). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL4A4: BP4, BS1, BS2 -
Likely 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	Invitae	Jan 31, 2024	- -

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. -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 01, 2017

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	3.9
Dann	Benign	0.85
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.12
Sift	Benign	0.96	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.58
MPC		0.12
ClinPred		0.0014	T
GERP RS		-0.43
Varity_R		0.023
gMVP		0.092

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: rs80243096; hg19: chr2-227917090;