X-108440180-C-G

Position:

• chrX-108440180-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033380.3(COL4A5):​c.55C>G​(p.Leu19Val) 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. 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: 1.22

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15220559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.55C>G	p.Leu19Val	missense_variant	1/53	ENST00000328300.11	NP_203699.1
COL4A5	NM_000495.5	c.55C>G	p.Leu19Val	missense_variant	1/51		NP_000486.1
COL4A5	XM_047441811.1	c.55C>G	p.Leu19Val	missense_variant	1/42		XP_047297767.1
COL4A5	XM_047441810.1	c.-322C>G		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.55C>G	p.Leu19Val	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

Oct 13, 2023

The c.55C>G (p.L19V) alteration is located in exon 1 (coding exon 1) of the COL4A5 gene. This alteration results from a C to G substitution at nucleotide position 55, causing the leucine (L) at amino acid position 19 to be replaced by a valine (V). 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	0.066
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.12	.;T
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.65	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.25
Sift	Benign	1.0	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0010	.;B
Vest4		0.21
MutPred		0.48		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.51
MPC		0.30
ClinPred		0.20	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.37

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-107683410;