X-108622766-G-T

Variant names:

• chrX-108622766-G-T
• rs78972735
• NM_033380.3:c.2858G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_033380.3(COL4A5):​c.2858G>T​(p.Gly953Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,209,432 control chromosomes in the GnomAD database, including 8 homozygotes. There are 474 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). Synonymous variant affecting the same amino acid position (i.e. G953G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., 71 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (8 hom. 403 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 7.25

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

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008373588).
• BP6: Variant X-108622766-G-T is Benign according to our data. Variant chrX-108622766-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24573.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=8}. Variant chrX-108622766-G-T is described in Lovd as [Likely_benign]. Variant chrX-108622766-G-T is described in Lovd as [Pathogenic]. Variant chrX-108622766-G-T is described in Lovd as [Likely_pathogenic]. Variant chrX-108622766-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00158 (178/112480) while in subpopulation EAS AF = 0.0374 (132/3529). AF 95% confidence interval is 0.0322. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position FAILED quality control check.
• BS2: High Hemizygotes in GnomAd4 at 71 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2858G>T	p.Gly953Val	missense_variant	Exon 33 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2858G>T	p.Gly953Val	missense_variant	Exon 33 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1682G>T	p.Gly561Val	missense_variant	Exon 17 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2858G>T	p.Gly953Val	missense_variant	Exon 33 of 51	2		ENSP00000354505.2
COL4A5	ENST00000505728.1	c.89G>T	p.Gly30Val	missense_variant	Exon 1 of 5	3		ENSP00000424137.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 179 AN: 112429 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000374

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0376

Gnomad SAS AF: 0.00661

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.00360 AC: 659 AN: 182930 AF XY: 0.00337

Gnomad AFR exome AF: 0.000533

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0368

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00104 AC: 1146 AN: 1096952 Hom.: 8 Cov.: 30 AF XY: 0.00111 AC XY: 403 AN XY: 362498

Gnomad4 AFR exome AF: 0.000227 AC: 6 AN: 26383

Gnomad4 AMR exome AF: 0.000114 AC: 4 AN: 35199

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19376

Gnomad4 EAS exome AF: 0.0223 AC: 673 AN: 30189

Gnomad4 SAS exome AF: 0.00529 AC: 286 AN: 54102

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40531

Gnomad4 NFE exome AF: 0.0000202 AC: 17 AN: 841334

Gnomad4 Remaining exome AF: 0.00348 AC: 160 AN: 46027

GnomAD4 genome AF: 0.00158 AC: 178 AN: 112480 Hom.: 0 Cov.: 23 AF XY: 0.00205 AC XY: 71 AN XY: 34670

Gnomad4 AFR AF: 0.000645 AC: 0.000644538 AN: 0.000644538

Gnomad4 AMR AF: 0.000374 AC: 0.000373867 AN: 0.000373867

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.0374 AC: 0.0374044 AN: 0.0374044

Gnomad4 SAS AF: 0.00663 AC: 0.00662739 AN: 0.00662739

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000375 AC: 0.0000375481 AN: 0.0000375481

Gnomad4 OTH AF: 0.00130 AC: 0.00130463 AN: 0.00130463

Alfa AF: 0.00102 Hom.: 7

Bravo AF: 0.00146

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00342 AC: 415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked Alport syndrome Uncertain:1 Benign:3

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Oct 28, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly953Val in exon 33 of COL4A5: This variant is not expected to have clinica l significance, because it has been identified in 3.7% (513/13865) of East Asian chromosomes including 7 homozygotes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104886203, rs78972735). Although it has been reported in several individuals with Alport syndrome or hearing loss, 2 individuals with Alport syndrome had another COL4A5 variant in cis with this va riant, and one individual was reported to have polycystic kidney disease with no additional clinical features of Alport syndrome (Knebelmann 1996, Lennon 2015, Miao 2017, Miyagawa 2013, Nishio 2015, Randles 2016, Tan 2010). In summary, it s frequency is too high to be causative for Alport syndrome. ACMG/AMP criteria a pplied: BA1 -

Dec 13, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Sep 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22995991, 28827396, 30577881, 30367527, 25739341, 23967202, 8940267, 30245029, 31138263, 28476686, 31180159, 32038292) -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kidney disorder Benign:1

Jun 24, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL4A5-related disorder Benign:1

Jun 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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	0.31
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.78
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.8	H;H;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.3	D;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.34
MVP		0.99
MPC		0.37
ClinPred		0.11	T
GERP RS		6.0
Varity_R		0.99
gMVP		1.0
Mutation Taster		=84/16	polymorphism (auto)

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: rs78972735; hg19: chrX-107865996;