rs61735627

chrX-108666560-T-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.3519T>G(p.Gly1173=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00577 in 1,206,410 control chromosomes in the GnomAD database, including 242 homozygotes. There are 1,861 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (120 hom., 910 hem., cov: 22)
  • Exomes 𝑓: 0.0033 (122 hom. 951 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.151

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-108666560-T-G is Benign according to our data. Variant chrX-108666560-T-G is described in ClinVar as [Benign]. Clinvar id is 256280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108666560-T-G is described in Lovd as [Benign]. Variant chrX-108666560-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.3519T>G	p.Gly1173=	synonymous_variant	39/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.3519T>G	p.Gly1173=	synonymous_variant	39/53	1	NM_033380.3
COL4A5	ENST00000361603.7	c.3519T>G	p.Gly1173=	synonymous_variant	39/51	2		P1

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 3364 AN: 112134 Hom.: 120 Cov.: 22 AF XY: 0.0263 AC XY: 902 AN XY: 34290

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000300

Gnomad OTH AF: 0.0199

GnomAD3 exomes AF: 0.00888 AC: 1542 AN: 173623 Hom.: 57 AF XY: 0.00549 AC XY: 326 AN XY: 59331

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000455

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00370

GnomAD4 exome AF: 0.00328 AC: 3587 AN: 1094222 Hom.: 122 Cov.: 30 AF XY: 0.00264 AC XY: 951 AN XY: 360102

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00701

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000281

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00708

GnomAD4 genome AF: 0.0301 AC: 3375 AN: 112188 Hom.: 120 Cov.: 22 AF XY: 0.0265 AC XY: 910 AN XY: 34354

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000301

Gnomad4 OTH AF: 0.0196

Alfa AF: 0.0159 Hom.: 82

Bravo AF: 0.0349

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

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.Gly1173Gly 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 12.25% (794/6480) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs61735627). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 16, 2021

- -

X-linked Alport syndrome Benign:1

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	7.6
Dann	Benign	0.73

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: rs61735627; hg19: chrX-107909790;