rs28935487

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000169.3(GLA):c.797A>T(p.Asp266Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,873 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D266H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.02

Variant links:

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]

GLA links:

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]

RPL36A-HNRNPH2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant X-101398789-T-A is Pathogenic according to our data. Variant chrX-101398789-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 10735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398789-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.797A>T	p.Asp266Val	missense_variant	Exon 5 of 7	ENST00000218516.4	NP_000160.1	P06280Q53Y83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 link	c.797A>T	p.Asp266Val	missense_variant	Exon 5 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+3332T>A		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111873

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34049

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111873

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34049

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:3

Jan 12, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLA c.797A>T (p.Asp266Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183472 control chromosomes. c.797A>T has been reported in the literature in multiple individuals affected with Fabry Disease (ie Eng_1993, Germain_2015, etc). These data indicate that the variant is very likely to be associated with disease. Experimental studies in cells expressing the variant have reported the variant to have absent alpha-Gal activity (Siekierska_2012, Wu_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

May 23, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.82

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

1.0

D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

5.0

H;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-8.9

D;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

1.0

MutPred

1.0

Loss of disorder (P = 0.2001);.;

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over