rs201679091

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000169.3(GLA):c.590G>A(p.Ser197Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,191,278 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S197S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.937

Publications

2 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: Uncertain_significance. The variant received 5 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, 18 uncertain in NM_000169.3

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.590G>A	p.Ser197Asn	missense_variant	Exon 4 of 7	ENST00000218516.4	NP_000160.1	P06280Q53Y83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 link	c.590G>A	p.Ser197Asn	missense_variant	Exon 4 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+5258C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000550

AC:

AN:

181847

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.0000769

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.27e-7

AC:

AN:

1079012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

346276

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:

26075

American (AMR)

AF:

0.00

AC:

AN:

35159

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19229

East Asian (EAS)

AF:

0.00

AC:

AN:

30121

South Asian (SAS)

AF:

0.00

AC:

AN:

53557

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40499

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4097

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

824814

Other (OTH)

AF:

0.00

AC:

AN:

45461

⚠️ 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: 0.375

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

AF:

0.00000891

AC:

AN:

112266

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34434

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30945

American (AMR)

AF:

0.00

AC:

AN:

10564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3601

South Asian (SAS)

AF:

0.00

AC:

AN:

2699

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53275

Other (OTH)

AF:

0.00

AC:

AN:

1542

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Uncertain:2

Feb 25, 2021

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine with asparagine at codon 197 of the GLA protein (p.Ser197Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with GLA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Jun 13, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S197N variant (also known as c.590G>A), located in coding exon 4 of the GLA gene, results from a G to A substitution at nucleotide position 590. The serine at codon 197 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/181847) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was < 0.01% (1/12997) of African alleles. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

CardioboostCm

Benign

0.0077

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.88

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.4

L;.

PhyloP100

0.94

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

N;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.0040

D;.

Polyphen

0.94

P;.

Vest4

0.56

MutPred

0.52

Loss of sheet (P = 0.1398);.;

MVP

0.90

MPC

0.67

ClinPred

0.76

GERP RS

5.4

Varity_R

0.83

gMVP

0.93

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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