rs104886107

Positions:

• chrX-108591091-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_033380.3(COL4A5):​c.1199G>A​(p.Gly400Glu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.19

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-108591091-G-A is Pathogenic according to our data. Variant chrX-108591091-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333248.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108591091-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1199G>A	p.Gly400Glu	missense_variant	20/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1199G>A	p.Gly400Glu	missense_variant	20/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.23G>A	p.Gly8Glu	missense_variant	4/20	1		ENSP00000495685
COL4A5	ENST00000361603.7	c.1199G>A	p.Gly400Glu	missense_variant	20/51	2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

COL4A5-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2024

The COL4A5 c.1199G>A variant is predicted to result in the amino acid substitution p.Gly400Glu. The p.Gly400 residue is located in the triple-helical region (residues 42 – 1456) of the COL4A5 protein (uniprot.org). The majority of pathogenic variants in COL4A5 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant was reported in an individual with Alport syndrome (Reported as 1402G>A, G400E in Boye et al 1995. PubMed ID: 7599631). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

X-linked Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.999, 3CNET: 0.963, PP3_P). A missense variant is a common mechanism associated with Alport syndrome 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.3	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.9	D;D;.
REVEL	Pathogenic	1.0
Sift	Uncertain	0.0020	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.99
MutPred		0.98		Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);.;
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.99

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: rs104886107; hg19: chrX-107834321;