X-108539746-G-T

Position:

• chrX-108539746-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_033380.3(COL4A5):​c.82G>T​(p.Ala28Ser) variant causes a missense, splice region 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. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A28T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense, splice_region
• Scores: Splicing: ADA: 0.09212
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.23

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108539746-G-T is Pathogenic according to our data. Variant chrX-108539746-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 222061.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108539746-G-T is described in Lovd as [Pathogenic]. Variant chrX-108539746-G-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.31417328). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.82G>T	p.Ala28Ser	missense_variant, splice_region_variant	2/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.82G>T	p.Ala28Ser	missense_variant, splice_region_variant	2/53	1	NM_033380.3
COL4A5	ENST00000361603.7	c.82G>T	p.Ala28Ser	missense_variant, splice_region_variant	2/51	2		P1
COL4A5	ENST00000470339.1	n.266G>T		splice_region_variant, non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Diagnostic Laboratory, University of Szeged

Feb 02, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.056	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.32	.;B
Vest4		0.42
MVP		0.75
MPC		0.27
ClinPred		0.58	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.092
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025333; hg19: chrX-107782976;