Genetic Variant GLA:p.Arg356Gln (chrX-101398032-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1PM5PP2PP3_ModerateBS2

The NM_000169.3(GLA):c.1067G>A(p.Arg356Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,209,095 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R356W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 3 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:10

Conservation

PhyloP100: 0.296

Publications

26 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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000169.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101398033-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10713.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, 0.906

BS2

High Hemizygotes in GnomAd4 at 2 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.1067G>A	p.Arg356Gln	missense	Exon 7 of 7	NP_000160.1	P06280
GLA	NM_001406747.1		c.1190G>A	p.Arg397Gln	missense	Exon 8 of 8	NP_001393676.1	A0A3B3IUC4
RPL36A-HNRNPH2	NM_001199973.2		c.300+2575C>T		intron	N/A	NP_001186902.2	H7BZ11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLA	ENST00000218516.4	TSL:1 MANE Select	c.1067G>A	p.Arg356Gln	missense	Exon 7 of 7	ENSP00000218516.4	P06280
RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2575C>T		intron	N/A	ENSP00000386655.4	H7BZ11
GLA	ENST00000649178.1		c.1190G>A	p.Arg397Gln	missense	Exon 8 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112005

Hom.:

Cov.:

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:

0.000281

Gnomad SAS

AF:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183292

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000760

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097090

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

362452

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26374

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30201

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.00000713

AC:

AN:

841088

Other (OTH)

AF:

0.0000434

AC:

AN:

46056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.0000268

AC:

AN:

112005

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34185

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30808

American (AMR)

AF:

0.00

AC:

AN:

10564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.000281

AC:

AN:

3555

South Asian (SAS)

AF:

0.000368

AC:

AN:

2721

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6053

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53228

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fabry disease (5)

not provided (3)

Cardiovascular phenotype (1)

GLA-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

CardioboostCm

Benign

0.021

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.94

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

0.17

PhyloP100

0.30

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.53

Sift

Benign

0.11

Sift4G

Benign

0.13

Polyphen

0.19

Vest4

0.12

MutPred

0.86

Loss of MoRF binding (P = 0.0857)

MVP

0.99

MPC

0.82

ClinPred

0.057

GERP RS

0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.81

Mutation Taster

=35/65

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over