rs7884085

Positions:

• chrX-108601898-T-C

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.2055T>C​(p.Leu685Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,152,504 control chromosomes in the GnomAD database, including 2,670 homozygotes. There are 7,507 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 (1308 hom., 3012 hem., cov: 22)
  • Exomes 𝑓: 0.016 (1362 hom. 4495 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.786

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-108601898-T-C is Benign according to our data. Variant chrX-108601898-T-C is described in ClinVar as [Benign]. Clinvar id is 24481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108601898-T-C is described in Lovd as [Benign]. Variant chrX-108601898-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.786 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2055T>C	p.Leu685Leu	synonymous_variant	27/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2055T>C	p.Leu685Leu	synonymous_variant	27/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.879T>C	p.Leu293Leu	synonymous_variant	11/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2055T>C	p.Leu685Leu	synonymous_variant	27/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes AF: 0.103 AC: 11409 AN: 110806 Hom.: 1308 Cov.: 22 AF XY: 0.0907 AC XY: 2998 AN XY: 33068

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.00303

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0889

GnomAD3 exomes AF: 0.0447 AC: 5777 AN: 129141 Hom.: 501 AF XY: 0.0332 AC XY: 1383 AN XY: 41639

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.0427

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.0162

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0157 AC: 16321 AN: 1041646 Hom.: 1362 Cov.: 25 AF XY: 0.0137 AC XY: 4495 AN XY: 327162

Gnomad4 AFR exome AF: 0.336

Gnomad4 AMR exome AF: 0.0466

Gnomad4 ASJ exome AF: 0.00372

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.000183

Gnomad4 NFE exome AF: 0.000601

Gnomad4 OTH exome AF: 0.0405

GnomAD4 genome AF: 0.103 AC: 11420 AN: 110858 Hom.: 1308 Cov.: 22 AF XY: 0.0909 AC XY: 3012 AN XY: 33130

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.0557

Gnomad4 ASJ AF: 0.00303

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.000166

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.0878

Alfa AF: 0.0576 Hom.: 509

Bravo AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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.Leu685Leu in exon 27 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 40.39% (1404/3476) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs7884085). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Eurofins Ntd Llc (ga)	Apr 07, 2016	- -

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	Mar 03, 2015	- -

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	-0.74
CADD	Benign	6.7
DANN	Benign	0.75

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: rs7884085; hg19: chrX-107845128;