rs61746140

Positions:

• chrX-108686107-C-T

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.4293C>T​(p.Asp1431Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,207,264 control chromosomes in the GnomAD database, including 2,328 homozygotes. There are 7,010 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (1150 hom., 2807 hem., cov: 23)
  • Exomes 𝑓: 0.014 (1178 hom. 4203 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0940

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]

COL4A5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant X-108686107-C-T is Benign according to our data. Variant chrX-108686107-C-T is described in ClinVar as [Benign]. Clinvar id is 24722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108686107-C-T is described in Lovd as [Benign]. Variant chrX-108686107-C-T is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=-0.094 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.4293C>T	p.Asp1431Asp	synonymous_variant	48/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4293C>T	p.Asp1431Asp	synonymous_variant	48/53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes AF: 0.0952 AC: 10543 AN: 110723 Hom.: 1150 Cov.: 23 AF XY: 0.0849 AC XY: 2799 AN XY: 32979

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.00305

Gnomad EAS AF: 0.0765

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.0779

GnomAD3 exomes AF: 0.0367 AC: 6680 AN: 181933 Hom.: 562 AF XY: 0.0256 AC XY: 1703 AN XY: 66619

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.0406

Gnomad ASJ exome AF: 0.00375

Gnomad EAS exome AF: 0.0773

Gnomad SAS exome AF: 0.00999

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000702

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0136 AC: 14923 AN: 1096486 Hom.: 1178 Cov.: 29 AF XY: 0.0116 AC XY: 4203 AN XY: 361958

Gnomad4 AFR exome AF: 0.322

Gnomad4 AMR exome AF: 0.0442

Gnomad4 ASJ exome AF: 0.00361

Gnomad4 EAS exome AF: 0.0806

Gnomad4 SAS exome AF: 0.00948

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.000511

Gnomad4 OTH exome AF: 0.0304

GnomAD4 genome AF: 0.0952 AC: 10547 AN: 110778 Hom.: 1150 Cov.: 23 AF XY: 0.0850 AC XY: 2807 AN XY: 33042

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.0527

Gnomad4 ASJ AF: 0.00305

Gnomad4 EAS AF: 0.0764

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.000167

Gnomad4 NFE AF: 0.00108

Gnomad4 OTH AF: 0.0769

Alfa AF: 0.0150 Hom.: 679

Bravo AF: 0.111

ClinVar

Significance: Benign

Submissions summary: Benign:8

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.Asp1431Asp in exon 48 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 36.69% (368/1003) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs61746140). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2018	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. -

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	-0.28
CADD	Benign	5.9
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61746140; hg19: chrX-107929337; COSMIC: COSV60360600;