rs3747408

Positions:

• chrX-108606846-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_033380.3(COL4A5):​c.2349G>A​(p.Pro783=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,208,260 control chromosomes in the GnomAD database, including 2,715 homozygotes. There are 8,298 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1298 hom., 3192 hem., cov: 22)
  • Exomes 𝑓: 0.016 (1417 hom. 5106 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0140

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant X-108606846-G-A is Benign according to our data. Variant chrX-108606846-G-A is described in ClinVar as [Benign]. Clinvar id is 24511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108606846-G-A is described in Lovd as [Benign]. Variant chrX-108606846-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.014 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2349G>A	p.Pro783=	synonymous_variant	29/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2349G>A	p.Pro783=	synonymous_variant	29/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.1173G>A	p.Pro391=	synonymous_variant	13/20	1		ENSP00000495685
COL4A5	ENST00000361603.7	c.2349G>A	p.Pro783=	synonymous_variant	29/51	2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 11569 AN: 110925 Hom.: 1298 Cov.: 22 AF XY: 0.0958 AC XY: 3179 AN XY: 33185

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.00303

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.0919

GnomAD3 exomes AF: 0.0454 AC: 8307 AN: 183121 Hom.: 698 AF XY: 0.0344 AC XY: 2326 AN XY: 67703

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.00374

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.0172

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0161 AC: 17647 AN: 1097288 Hom.: 1417 Cov.: 30 AF XY: 0.0141 AC XY: 5106 AN XY: 362670

Gnomad4 AFR exome AF: 0.340

Gnomad4 AMR exome AF: 0.0470

Gnomad4 ASJ exome AF: 0.00361

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.000607

Gnomad4 OTH exome AF: 0.0397

GnomAD4 genome AF: 0.104 AC: 11579 AN: 110972 Hom.: 1298 Cov.: 22 AF XY: 0.0960 AC XY: 3192 AN XY: 33242

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.0565

Gnomad4 ASJ AF: 0.00303

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.0212

Gnomad4 FIN AF: 0.000168

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.0908

Alfa AF: 0.0452 Hom.: 503

Bravo AF: 0.121

EpiCase AF: 0.000818

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro783Pro in exon 29 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 39.48% (396/1003) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs3747408). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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 21, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	7.1
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3747408; hg19: chrX-107850076; COSMIC: COSV60358321;