rs869312156

Variant names:

• chrX-101398426-C-T
• rs869312156
• NM_000169.3:c.943G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. 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).

• 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:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• 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 rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.943G>A	p.Asp315Asn	missense_variant	Exon 6 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.943G>A	p.Asp315Asn	missense_variant	Exon 6 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2969C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

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

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Migalastat response Other:1

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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;.
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;