rs2272945

chrX-108586677-G-CchrX-108586677-G-T

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.1095G>C(p.Gly365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 1,205,928 control chromosomes in the GnomAD database, including 2,808 homozygotes. There are 8,319 hemizygotes in GnomAD. 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. G365G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1347 hom., 3194 hem., cov: 22)
  • Exomes 𝑓: 0.016 (1461 hom. 5125 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.895

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=-0.74).
• BP6: Variant X-108586677-G-C is Benign according to our data. Variant chrX-108586677-G-C is described in ClinVar as [Benign]. Clinvar id is 24365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108586677-G-C is described in Lovd as [Benign]. Variant chrX-108586677-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.895 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.1095G>C	p.Gly365=	synonymous_variant	19/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.1095G>C	p.Gly365=	synonymous_variant	19/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.-82G>C		5_prime_UTR_variant	3/20	1
COL4A5	ENST00000361603.7	c.1095G>C	p.Gly365=	synonymous_variant	19/51	2		P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 11721 AN: 110336 Hom.: 1347 Cov.: 22 AF XY: 0.0973 AC XY: 3179 AN XY: 32672

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0563

Gnomad ASJ AF: 0.00304

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0894

GnomAD3 exomes AF: 0.0458 AC: 8396 AN: 183258 Hom.: 733 AF XY: 0.0344 AC XY: 2332 AN XY: 67748

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.0437

Gnomad ASJ exome AF: 0.00374

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.0174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000843

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0162 AC: 17771 AN: 1095540 Hom.: 1461 Cov.: 30 AF XY: 0.0142 AC XY: 5125 AN XY: 361180

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.0470

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.000605

Gnomad4 OTH exome AF: 0.0399

GnomAD4 genome AF: 0.106 AC: 11733 AN: 110388 Hom.: 1347 Cov.: 22 AF XY: 0.0976 AC XY: 3194 AN XY: 32734

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.0560

Gnomad4 ASJ AF: 0.00304

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.0208

Gnomad4 FIN AF: 0.000168

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.0883

Alfa AF: 0.0156 Hom.: 102

Bravo AF: 0.123

EpiCase AF: 0.000928

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.Gly365Gly in exon 19 of COL4A5: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 40.08% (402/1003) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs2272945). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

X-linked Alport syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 26, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.2
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2272945; hg19: chrX-107829907; COSMIC: COSV60358314;