rs146177035

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000169.3(GLA):c.129C>T(p.Gly43Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,209,678 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 0 hom. 29 hem. )

Consequence

GLA
NM_000169.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.17

Publications

0 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant X-101407775-G-A is Benign according to our data. Variant chrX-101407775-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.17 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000232 (26/112243) while in subpopulation EAS AF = 0.00365 (13/3562). AF 95% confidence interval is 0.00216. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.129C>T	p.Gly43Gly	synonymous_variant	Exon 1 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.129C>T	p.Gly43Gly	synonymous_variant	Exon 1 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3 link	c.301-4161G>A		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

112191

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000939

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00364

Gnomad SAS

AF:

0.000737

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.000662

GnomAD2 exomes

AF:

0.000463

AC:

AN:

183430

AF XY:

0.000354

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00527

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000611

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000107

AC:

117

AN:

1097435

Hom.:

Cov.:

AF XY:

0.0000799

AC XY:

AN XY:

362797

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26391

American (AMR)

AF:

0.0000568

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00268

AC:

AN:

30203

South Asian (SAS)

AF:

0.0000739

AC:

AN:

54129

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000166

AC:

AN:

841384

Other (OTH)

AF:

0.000326

AC:

AN:

46074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.000232

AC:

AN:

112243

Hom.:

Cov.:

AF XY:

0.000262

AC XY:

AN XY:

34405

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30941

American (AMR)

AF:

0.0000937

AC:

AN:

10668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00365

AC:

AN:

3562

South Asian (SAS)

AF:

0.000740

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6135

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000753

AC:

AN:

53151

Other (OTH)

AF:

0.000654

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000116

Hom.:

Bravo

AF:

0.000264

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 28, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 12, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 15, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The GLA c.129C>T (p.Gly43Gly) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect any ESE site. This variant was found in 30/87749 control chromosomes in ExAC database, including 7 hemizygotes (~1 in 4179 males, assuming male/female ratio is 1). Fabry disease affects an estimated 1 in 40,000 to 60,000 males (https://ghr.nlm.nih.gov/condition/fabry-disease#statistics), which is much lower than the hemizygote frequency of the variant of interest. Therefore, this variant is unlikely to associate with the disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Fabry disease

Benign:3

May 29, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Apr 25, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

2.2

PromoterAI

0.0028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=51/49

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over