rs2272946

Positions:

• chrX-108591223-T-A
• chrX-108591223-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_033380.3(COL4A5):​c.1331T>A​(p.Ile444Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I444S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10

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 2 ACMG points.

• PM1: In a compositionally_biased_region Pro residues (size 47) in uniprot entity CO4A5_HUMAN there are 20 pathogenic changes around while only 6 benign (77%) in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24169609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.1331T>A	p.Ile444Asn	missense_variant	20/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.1331T>A	p.Ile444Asn	missense_variant	20/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.155T>A	p.Ile52Asn	missense_variant	4/20	1
COL4A5	ENST00000361603.7	c.1331T>A	p.Ile444Asn	missense_variant	20/51	2		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.5
DANN	Benign	0.49
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	-0.077	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.19	N;N;.
REVEL	Benign	0.17
Sift	Benign	0.35	T;T;.
Sift4G	Benign	0.31	T;T;.
Polyphen		0.37	.;B;B
Vest4		0.31
MutPred		0.61		Gain of catalytic residue at I444 (P = 0.0179);Gain of catalytic residue at I444 (P = 0.0179);.;
MVP		0.52
MPC		0.53
ClinPred		0.21	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.27
gMVP		0.70

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: rs2272946; hg19: chrX-107834453;