X-101398859-A-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.727T>A(p.Leu243Met) 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. 13/21 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. L243F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0730

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=0.34075803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.727T>A	p.Leu243Met	missense_variant	5/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+3402A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.727T>A	p.Leu243Met	missense_variant	5/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostCm	Benign	0.024
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	20
Dann	Benign	0.89
DEOGEN2	Uncertain	0.76	D;.
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.91	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.33	T;.
Sift4G	Benign	0.24	T;.
Polyphen		0.73	P;.
Vest4		0.40
MutPred		0.62		Loss of catalytic residue at L243 (P = 0.047);.;
MVP		0.94
MPC		1.1
ClinPred		0.50	D
GERP RS		3.3
Varity_R		0.44
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782453201; hg19: chrX-100653847;