chrX-101398426-C-T

Position:

• chrX-101398426-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000169.3(GLA):​c.943G>A​(p.Asp315Asn) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,drug response (no stars). Synonymous variant affecting the same amino acid position (i.e. D315D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance; drug response no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 0.797

Genes affected

GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

RPL36A-HNRNPH2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.370162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.943G>A	p.Asp315Asn	missense_variant	6/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+2969C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.943G>A	p.Asp315Asn	missense_variant	6/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance; drug response

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Fabry disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- -

Migalastat response Other:1

drug response, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- Pharmacological Chaperone response: yes

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
CardioboostCm	Uncertain	0.19
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.92	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.71	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.32	T;.
Sift4G	Benign	0.32	T;.
Polyphen		0.0080	B;.
Vest4		0.39
MutPred		0.41		Gain of methylation at K314 (P = 0.055);.;
MVP		0.90
MPC		0.69
ClinPred		0.25	T
GERP RS		5.8
Varity_R		0.37
gMVP		0.89

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: rs869312156; hg19: chrX-100653414;