Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000169.3(GLA):c.979C>A(p.Gln327Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Q327H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.99

Publications

13 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 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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-101398388-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4087611.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

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant X-101398390-G-T is Pathogenic according to our data. Variant chrX-101398390-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10739.Status of the report is criteria_provided_single_submitter, 1 stars.

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
GLA	NM_000169.3	MANE Select	c.979C>A	p.Gln327Lys	missense	Exon 6 of 7	NP_000160.1
GLA	NM_001406747.1		c.1102C>A	p.Gln368Lys	missense	Exon 7 of 8	NP_001393676.1
GLA	NM_001406748.1		c.979C>A	p.Gln327Lys	missense	Exon 6 of 6	NP_001393677.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLA	ENST00000218516.4	TSL:1 MANE Select	c.979C>A	p.Gln327Lys	missense	Exon 6 of 7	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2933G>T		intron	N/A	ENSP00000386655.4
GLA	ENST00000649178.1		c.1102C>A	p.Gln368Lys	missense	Exon 7 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1093779

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359369

African (AFR)

AF:

0.00

AC:

AN:

26318

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19359

East Asian (EAS)

AF:

0.00

AC:

AN:

30192

South Asian (SAS)

AF:

0.00

AC:

AN:

54048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4098

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838092

Other (OTH)

AF:

0.00

AC:

AN:

45967

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fabry disease (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

CardioboostCm

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.68

BayesDel_noAF

Pathogenic

0.74

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

4.7

PhyloP100

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.90

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.90

MutPred

0.88

Gain of ubiquitination at Q327 (P = 0.0219)

MVP

1.0

MPC

2.0

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.99

Mutation Taster

=32/68

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over