NM_000169.3:c.1176G>T

Variant names:

• chrX-101397923-C-A
• rs869312165
• NM_000169.3:c.1176G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000169.3(GLA):​c.1176G>T​(p.Arg392Ser) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R392T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Likely pathogenic; drug response no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.218
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16453326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.1176G>T	p.Arg392Ser	missense_variant	Exon 7 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.1176G>T	p.Arg392Ser	missense_variant	Exon 7 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2466C>A		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic; drug response

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Fabry disease Pathogenic:1

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Likely pathogenic

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: no

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostCm	Benign	0.016
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.6
DANN	Benign	0.70
DEOGEN2	Uncertain	0.73	D;.
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.45	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Pathogenic	2.1	D
MutationAssessor	Benign	1.7	L;.
PhyloP100		0.22
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.31
Sift	Benign	0.73	T;.
Sift4G	Benign	0.70	T;.
Polyphen		0.0010	B;.
Vest4		0.14
MutPred		0.52		Loss of methylation at K391 (P = 0.0391);.;
MVP		0.85
MPC		0.80
ClinPred		0.026	T
GERP RS		-0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.78
Mutation Taster		=29/71	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869312165; hg19: chrX-100652911;