rs78972735

Positions:

• chrX-108622766-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. 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

Verdict is Benign. Variant got -13 ACMG points.

• 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: {Benign=9, Uncertain_significance=1}. 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 71 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.2858G>T	p.Gly953Val	missense_variant	33/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.2858G>T	p.Gly953Val	missense_variant	33/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.1682G>T	p.Gly561Val	missense_variant	17/20	1
COL4A5	ENST00000361603.7	c.2858G>T	p.Gly953Val	missense_variant	33/51	2		P1
COL4A5	ENST00000505728.1	c.92G>T	p.Gly31Val	missense_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 179 AN: 112429 Hom.: 0 Cov.: 23 AF XY: 0.00208 AC XY: 72 AN XY: 34609

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

GnomAD3 exomes AF: 0.00360 AC: 659 AN: 182930 Hom.: 7 AF XY: 0.00337 AC XY: 228 AN XY: 67596

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 SAS exome AF: 0.00650

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

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0223

Gnomad4 SAS exome AF: 0.00529

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.00348

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

Gnomad4 AMR AF: 0.000374

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0374

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00107 Hom.: 5

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

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2017	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 -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 13, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2019	This variant is associated with the following publications: (PMID: 22995991, 28827396, 30577881, 30367527, 25739341, 23967202, 8940267, 30245029, 31138263, 28476686, 31180159, 32038292) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 24, 2021

- -

COL4A5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2022

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
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;.
MutationTaster	Benign	1.0	A;A
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

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;