X-108440128-G-T

Position:

• chrX-108440128-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_033380.3(COL4A5):​c.3G>T​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: COL4A5 NM_033380.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.04

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108440128-G-T is Pathogenic according to our data. Variant chrX-108440128-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2770173.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108440128-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.3G>T	p.Met1?	start_lost	1/53	ENST00000328300.11	NP_203699.1
COL4A5	NM_000495.5	c.3G>T	p.Met1?	start_lost	1/51		NP_000486.1
COL4A5	XM_047441811.1	c.3G>T	p.Met1?	start_lost	1/42		XP_047297767.1
COL4A5	XM_047441810.1	c.-374G>T		5_prime_UTR_variant	1/54		XP_047297766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.3G>T	p.Met1?	start_lost	1/53	1	NM_033380.3	ENSP00000331902

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the COL4A5 protein in which other variant(s) (p.Gly54Arg) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Disruption of the initiator codon has been observed in individuals with Alport syndrome (PMID: 24033287; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the COL4A5 mRNA. The next in-frame methionine is located at codon 109. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.84	N;N
REVEL	Uncertain	0.62
Sift	Benign	0.031	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.53	.;P
Vest4		0.88
MutPred		0.90		Loss of MoRF binding (P = 0.078);Loss of MoRF binding (P = 0.078);
MVP		1.0
ClinPred		0.96	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107683358;