rs3027585

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000169.3(GLA):c.-12G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,200,657 control chromosomes in the GnomAD database, including 1,251 homozygotes. There are 16,901 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 0.066 ( 281 hom., 2123 hem., cov: 23)

Exomes 𝑓: 0.040 ( 970 hom. 14778 hem. )

Consequence

GLA
NM_000169.3 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.576

Publications

18 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant X-101407915-C-T is Benign according to our data. Variant chrX-101407915-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 42449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407915-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 42449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407915-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 42449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407915-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 42449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.-12G>A		5_prime_UTR_variant	Exon 1 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.-12G>A		5_prime_UTR_variant	Exon 1 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.301-4021C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.0658

AC:

7361

AN:

111875

Hom.:

280

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.0116

Gnomad AMR

AF:

0.0895

Gnomad ASJ

AF:

0.00869

Gnomad EAS

AF:

0.0377

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.00717

Gnomad MID

AF:

0.0335

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0693

GnomAD2 exomes

AF:

0.0607

AC:

11095

AN:

182916

AF XY:

0.0577

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.134

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.0398

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.0288

Gnomad OTH exome

AF:

0.0531

GnomAD4 exome

AF:

0.0398

AC:

43354

AN:

1088727

Hom.:

970

Cov.:

AF XY:

0.0417

AC XY:

14778

AN XY:

354697

show subpopulations

African (AFR)

AF:

0.147

AC:

3849

AN:

26210

American (AMR)

AF:

0.130

AC:

4580

AN:

35154

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

266

AN:

19335

East Asian (EAS)

AF:

0.0461

AC:

1391

AN:

30165

South Asian (SAS)

AF:

0.115

AC:

6178

AN:

53829

European-Finnish (FIN)

AF:

0.00948

AC:

384

AN:

40520

Middle Eastern (MID)

AF:

0.0491

AC:

187

AN:

3805

European-Non Finnish (NFE)

AF:

0.0293

AC:

24446

AN:

833971

Other (OTH)

AF:

0.0453

AC:

2073

AN:

45738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1398

2796

4195

5593

6991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1096

2192

3288

4384

5480

<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:

0.0659

AC:

7374

AN:

111930

Hom.:

281

Cov.:

AF XY:

0.0622

AC XY:

2123

AN XY:

34134

show subpopulations

African (AFR)

AF:

0.142

AC:

4350

AN:

30663

American (AMR)

AF:

0.0892

AC:

948

AN:

10626

Ashkenazi Jewish (ASJ)

AF:

0.00869

AC:

AN:

2647

East Asian (EAS)

AF:

0.0378

AC:

134

AN:

3544

South Asian (SAS)

AF:

0.117

AC:

316

AN:

2691

European-Finnish (FIN)

AF:

0.00717

AC:

AN:

6134

Middle Eastern (MID)

AF:

0.0367

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0271

AC:

1440

AN:

53200

Other (OTH)

AF:

0.0678

AC:

103

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

230

460

691

921

1151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0606

Hom.:

1027

Bravo

AF:

0.0764

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Apr 17, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

-12G>A in the 5' UTR of GLA: This variant is not expected to have clinical signi ficance because it has been identified in 14.5% (467/3216) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs3027585) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 11, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Dec 30, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25772321) -

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:4

Mar 19, 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

- -

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hypertrophic cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.81

(source)

DANN

Benign

0.75

PhyloP100

-0.58

PromoterAI

0.059

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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