rs104886192

Positions:

• chrX-108621817-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The ENST00000328300.11(COL4A5):​c.2692A>G​(p.Met898Val) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,203,910 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 85 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00022 (0 hom. 77 hem.)
• Consequence: COL4A5 ENST00000328300.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 B:7
• Conservation: PhyloP100: 5.54

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 0 uncertain in ENST00000328300.11
• BP4: Computational evidence support a benign effect (MetaRNN=0.053881973).
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2692A>G	p.Met898Val	missense_variant	32/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2692A>G	p.Met898Val	missense_variant	32/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.1516A>G	p.Met506Val	missense_variant	16/20	1		ENSP00000495685
COL4A5	ENST00000361603.7	c.2692A>G	p.Met898Val	missense_variant	32/51	2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112245 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34395

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00339

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000304 AC: 55 AN: 181177 Hom.: 0 AF XY: 0.000425 AC XY: 28 AN XY: 65893

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00324

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000811

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000224 AC: 244 AN: 1091665 Hom.: 0 Cov.: 28 AF XY: 0.000215 AC XY: 77 AN XY: 357385

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000856

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000196 AC: 22 AN: 112245 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34395

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00339

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00147

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000604 Hom.: 5

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000297 AC: 36

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked Alport syndrome Pathogenic:2 Uncertain:1 Benign:2

Uncertain significance, flagged submission	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	May 01, 2024	Pathogenic by Deafness Variation Database based on PMID:30773290 -
Pathogenic, flagged submission	clinical testing	Medical Genetics, University of Parma	Mar 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Aug 30, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 15, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2020	This variant is associated with the following publications: (PMID: 30773290, 11223851, 25525159, 20378821) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	COL4A5: BS2 -

Autosomal dominant Alport syndrome Pathogenic:1

Pathogenic, flagged submission

literature only

Yale Center for Mendelian Genomics, Yale University

Feb 14, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 01, 2024

Variant summary: COL4A5 c.2692A>G (p.Met898Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 1203910 control chromosomes, including 85 hemizygotes (gnomAD v4.1.0). c.2692A>G has been reported in the literature in individuals with clinical features of Alport syndrome (e.g., Barker_2001, Connaughton_2019, Uliana_2021), however these report(s) do not provide unequivocal conclusions about association of the variant with Alport Syndrome 1, X-Linked Recessive. Co-occurrences with other pathogenic variant(s) have been reported (INF2 c.353T>A, p.Ile118Asn), providing supporting evidence for a benign role (Connaughton_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11223851, 30773290, 33369211). ClinVar contains an entry for this variant (Variation ID: 24554). Based on the evidence outlined above, the variant was classified as likely benign. -

COL4A5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	.;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.45	N;N;.
MutationTaster	Benign	0.98	A;A
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.21	T;T;.
Sift4G	Benign	0.60	T;T;.
Polyphen		0.0050, 0.0030	.;B;B
Vest4		0.17
MVP		0.99
MPC		0.30
ClinPred		0.051	T
GERP RS		4.5
Varity_R		0.26
gMVP		0.86

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: rs104886192; hg19: chrX-107865047;