Genetic Variant GLA:p.Ile289Val (chrX-101398504-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 5P and 11B. PM1PM5PP2BP4_ModerateBP6BS1BS2

The NM_000169.3(GLA):c.865A>G(p.Ile289Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,206,911 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign 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. I289F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000027 ( 0 hom. 8 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6O:1

Conservation

PhyloP100: 3.46

Publications

12 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: Likely_benign. The variant received -6 ACMG points.

PM1

In a hotspot region, there are 42 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000169.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101398504-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92568.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.15808281).

BP6

Variant X-101398504-T-C is Benign according to our data. Variant chrX-101398504-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217400.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000892 (10/112075) while in subpopulation AMR AF = 0.000284 (3/10552). AF 95% confidence interval is 0.000106. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 6 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
GLA	NM_000169.3	MANE Select	c.865A>G	p.Ile289Val	missense	Exon 6 of 7	NP_000160.1
GLA	NM_001406747.1		c.988A>G	p.Ile330Val	missense	Exon 7 of 8	NP_001393676.1
GLA	NM_001406748.1		c.865A>G	p.Ile289Val	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.865A>G	p.Ile289Val	missense	Exon 6 of 7	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3047T>C		intron	N/A	ENSP00000386655.4
GLA	ENST00000649178.1		c.988A>G	p.Ile330Val	missense	Exon 7 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes

AF:

0.0000982

AC:

AN:

112019

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000380

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

GnomAD2 exomes

AF:

0.000158

AC:

AN:

183467

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.000948

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1094836

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

360252

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26325

American (AMR)

AF:

0.000710

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.00

AC:

AN:

54077

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839051

Other (OTH)

AF:

0.00

AC:

AN:

45977

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000892

AC:

AN:

112075

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34257

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

30861

American (AMR)

AF:

0.000284

AC:

AN:

10552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53251

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000795

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000148

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fabry disease (7)

not provided (2)

Cardiovascular phenotype (1)

GLA-related disorder (1)

not specified (1)

Migalastat response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

CardioboostCm

Uncertain

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.16

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.2

PhyloP100

3.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.85

REVEL

Uncertain

0.62

Sift

Benign

0.23

Sift4G

Benign

0.18

Polyphen

0.97

Vest4

0.76

MVP

0.87

MPC

0.60

ClinPred

0.13

GERP RS

4.7

Varity_R

0.46

gMVP

0.94

Mutation Taster

=52/48

polymorphism

(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