rs2273051

Positions:

• chrX-108666554-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033380.3(COL4A5):​c.3513A>G​(p.Gln1171=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,206,703 control chromosomes in the GnomAD database, including 4,546 homozygotes. There are 10,141 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2237 hom., 4190 hem., cov: 23)
  • Exomes 𝑓: 0.019 (2309 hom. 5951 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.25

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. 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. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-108666554-A-G is Benign according to our data. Variant chrX-108666554-A-G is described in ClinVar as [Benign]. Clinvar id is 24640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108666554-A-G is described in Lovd as [Benign]. Variant chrX-108666554-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.3513A>G	p.Gln1171=	synonymous_variant	39/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.3513A>G	p.Gln1171=	synonymous_variant	39/53	1	NM_033380.3
COL4A5	ENST00000361603.7	c.3513A>G	p.Gln1171=	synonymous_variant	39/51	2		P1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 15038 AN: 111833 Hom.: 2236 Cov.: 23 AF XY: 0.122 AC XY: 4165 AN XY: 34011

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.00302

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.0529 AC: 9226 AN: 174423 Hom.: 1098 AF XY: 0.0360 AC XY: 2162 AN XY: 60047

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.0484

Gnomad ASJ exome AF: 0.00381

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.0168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0192 AC: 21073 AN: 1094812 Hom.: 2309 Cov.: 30 AF XY: 0.0165 AC XY: 5951 AN XY: 360648

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.0532

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.000174

Gnomad4 NFE exome AF: 0.000737

Gnomad4 OTH exome AF: 0.0466

GnomAD4 genome AF: 0.135 AC: 15063 AN: 111891 Hom.: 2237 Cov.: 23 AF XY: 0.123 AC XY: 4190 AN XY: 34079

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.0662

Gnomad4 ASJ AF: 0.00302

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.0233

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0284 Hom.: 873

Bravo AF: 0.155

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gln1171Gln in exon 39 of COL4A5: 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 47.64% (3343/7017 ) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs2273051). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

X-linked Alport syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 21, 2020	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.8
DANN	Benign	0.64

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: rs2273051; hg19: chrX-107909784; COSMIC: COSV60358057; COSMIC: COSV60358057;