Genetic Variant GLA:p.Arg112His (chrX-101403845-C-T) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 17P and 4B. PM1PM5PP2PP3_StrongPP5_Very_StrongBS2

The NM_000169.3(GLA):c.335G>A(p.Arg112His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,210,198 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000018 ( 0 hom. 8 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 7.71

Publications

91 publications found

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 was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 uncertain in NM_000169.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101403846-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4081422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant X-101403845-C-T is Pathogenic according to our data. Variant chrX-101403845-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 195028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 8 XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLA	NM_000169.3	MANE Select	c.335G>A	p.Arg112His	missense	Exon 2 of 7	NP_000160.1	P06280
GLA	NM_001406747.1		c.458G>A	p.Arg153His	missense	Exon 3 of 8	NP_001393676.1	A0A3B3IUC4
GLA	NM_001406748.1		c.335G>A	p.Arg112His	missense	Exon 2 of 6	NP_001393677.1	A0A6Q8PHD1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLA	ENST00000218516.4	TSL:1 MANE Select	c.335G>A	p.Arg112His	missense	Exon 2 of 7	ENSP00000218516.4	P06280
RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-8091C>T		intron	N/A	ENSP00000386655.4	H7BZ11
GLA	ENST00000649178.1		c.458G>A	p.Arg153His	missense	Exon 3 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183395

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1097538

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

362900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26392

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000214

AC:

AN:

841481

Other (OTH)

AF:

0.0000434

AC:

AN:

46074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112660

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31017

American (AMR)

AF:

0.00

AC:

AN:

10650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3606

South Asian (SAS)

AF:

0.00

AC:

AN:

2782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6201

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53311

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fabry disease (15)

not provided (7)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

CardioboostCm

Uncertain

0.74

BayesDel_addAF

Pathogenic

0.64

BayesDel_noAF

Pathogenic

0.79

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.3

PhyloP100

7.7

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.89

MVP

1.0

MPC

2.0

ClinPred

0.96

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over