chrX-108621871-A-G

Position:

• chrX-108621871-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_033380.3(COL4A5):​c.2746A>G​(p.Ser916Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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:1
• Conservation: PhyloP100: 3.39

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108621871-A-G is Pathogenic according to our data. Variant chrX-108621871-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3389457.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108621871-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2746A>G	p.Ser916Gly	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.2746A>G	p.Ser916Gly	missense_variant	32/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1570A>G	p.Ser524Gly	missense_variant	16/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2746A>G	p.Ser916Gly	missense_variant	32/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

COL4A5: PM2, PS4:Moderate, PP4, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;D;T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Uncertain	0.42
Sift	Benign	0.066	T;D;.
Sift4G	Benign	0.069	T;T;.
Polyphen		0.10, 0.27	.;B;B
Vest4		0.77
MutPred		0.27		Loss of phosphorylation at S916 (P = 0.0082);Loss of phosphorylation at S916 (P = 0.0082);.;
MVP		0.95
MPC		0.28
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.32
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs104886193; hg19: chrX-107865101;