X-101400667-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate

The NM_000169.3(GLA):c.638A>G(p.Lys213Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. 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. K213N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000010 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GLA
NM_000169.3 missense, splice_region

Scores

Splicing: ADA: 0.9980

Clinical Significance

Pathogenic; drug response no assertion criteria provided P:1O:1

Conservation

PhyloP100: 5.36

Publications

9 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000169.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101400666-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4087445.Status of the report is criteria_provided_single_submitter, 1 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

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant X-101400667-T-C is Pathogenic according to our data. Variant chrX-101400667-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 217391.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.638A>G	p.Lys213Arg	missense_variant, splice_region_variant	Exon 4 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 link	c.638A>G	p.Lys213Arg	missense_variant, splice_region_variant	Exon 4 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+5210T>C		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.98e-7

AC:

AN:

1002340

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

299570

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24606

American (AMR)

AF:

0.00

AC:

AN:

34994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18713

East Asian (EAS)

AF:

0.00

AC:

AN:

29776

South Asian (SAS)

AF:

0.0000193

AC:

AN:

51786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3928

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

755180

Other (OTH)

AF:

0.00

AC:

AN:

42987

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:1

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: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

0.092

CardioboostCm

Benign

0.015

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

D;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Pathogenic

1.2

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

5.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

N;.

REVEL

Uncertain

0.47

Sift

Benign

0.18

T;.

Sift4G

Benign

0.15

T;.

Polyphen

0.20

B;.

Vest4

0.25

MutPred

0.49

Loss of methylation at K213 (P = 0.0096);.;

MVP

0.96

MPC

0.58

ClinPred

0.73

GERP RS

5.4

Varity_R

0.46

gMVP

0.86

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.73

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.73

Position offset: -1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over