X-108440171-G-C

Position:

• chrX-108440171-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033380.3(COL4A5):​c.46G>C​(p.Ala16Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.46G>C	p.Ala16Pro	missense_variant	1/53	ENST00000328300.11	NP_203699.1
COL4A5	NM_000495.5	c.46G>C	p.Ala16Pro	missense_variant	1/51		NP_000486.1
COL4A5	XM_047441811.1	c.46G>C	p.Ala16Pro	missense_variant	1/42		XP_047297767.1
COL4A5	XM_047441810.1	c.-331G>C		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.46G>C	p.Ala16Pro	missense_variant	1/53	1	NM_033380.3	ENSP00000331902

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.46G>C (p.A16P) alteration is located in exon 1 (coding exon 1) of the COL4A5 gene. This alteration results from a G to C substitution at nucleotide position 46, causing the alanine (A) at amino acid position 16 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.70	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.20	T;T
Sift4G	Benign	0.11	T;T
Polyphen		1.0	.;D
Vest4		0.73
MutPred		0.73		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP		0.96
MPC		0.39
ClinPred		0.71	D
GERP RS		4.7
Varity_R		0.53
gMVP		0.51

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-107683401;