rs782449839

Variant names:

• chrX-101397903-C-A
• rs782449839
• NM_000169.3:c.1196G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-101397903-C-A
• chrX-101397903-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000169.3(GLA):​c.1196G>T​(p.Trp399Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W399S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.44
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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=0.35456818).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.1196G>T	p.Trp399Leu	missense	Exon 7 of 7	NP_000160.1
	GLA	NM_001406747.1		c.1319G>T	p.Trp440Leu	missense	Exon 8 of 8	NP_001393676.1
	GLA	NR_164783.1		n.1275G>T		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.1196G>T	p.Trp399Leu	missense	Exon 7 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2446C>A		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.1319G>T	p.Trp440Leu	missense	Exon 8 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
CardioboostCm	Benign	0.042
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Benign	0.72
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.35	T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.42
Sift	Benign	0.70	T
Sift4G	Benign	0.81	T
Polyphen		0.0040	B
Vest4		0.52
MutPred		0.52		Loss of MoRF binding (P = 0.0308)
MVP		0.85
MPC		1.2
ClinPred		0.47	T
GERP RS		5.4
Varity_R		0.47
gMVP		0.91
Mutation Taster		=90/10	polymorphism

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: rs782449839; hg19: chrX-100652891;