Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 7P and 9B. PM1PM5PP2PP3_ModerateBP6BS1BS2

The NM_000169.3(GLA):c.196G>C(p.Glu66Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,203,291 control chromosomes in the GnomAD database, including 2 homozygotes. There are 49 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. E66G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 2 hom. 49 hem. )

Consequence

GLA
NM_000169.3 missense, splice_region

Scores

Splicing: ADA: 0.9018

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:5

Conservation

PhyloP100: 7.86

Publications

90 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 -2 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, 11 uncertain in NM_000169.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101403983-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2689132.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, 0.908

BP6

Variant X-101403984-C-G is Benign according to our data. Variant chrX-101403984-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163548.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000356 (4/112380) while in subpopulation EAS AF = 0.00111 (4/3589). AF 95% confidence interval is 0.00038. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 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
GLA	NM_000169.3	MANE Select	c.196G>C	p.Glu66Gln	missense splice_region	Exon 2 of 7	NP_000160.1
GLA	NM_001406747.1		c.319G>C	p.Glu107Gln	missense splice_region	Exon 3 of 8	NP_001393676.1
GLA	NM_001406748.1		c.196G>C	p.Glu66Gln	missense splice_region	Exon 2 of 6	NP_001393677.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLA	ENST00000218516.4	TSL:1 MANE Select	c.196G>C	p.Glu66Gln	missense splice_region	Exon 2 of 7	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-7952C>G		intron	N/A	ENSP00000386655.4
GLA	ENST00000649178.1		c.319G>C	p.Glu107Gln	missense splice_region	Exon 3 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112326

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00111

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:

0.000115

AC:

AN:

182566

AF XY:

0.0000745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00152

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

155

AN:

1090911

Hom.:

Cov.:

AF XY:

0.000137

AC XY:

AN XY:

356565

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26288

American (AMR)

AF:

0.0000284

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19352

East Asian (EAS)

AF:

0.00507

AC:

153

AN:

30189

South Asian (SAS)

AF:

0.00

AC:

AN:

53991

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40301

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

835608

Other (OTH)

AF:

0.0000218

AC:

AN:

45868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000356

AC:

AN:

112380

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34568

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30966

American (AMR)

AF:

0.00

AC:

AN:

10601

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00111

AC:

AN:

3589

South Asian (SAS)

AF:

0.00

AC:

AN:

2737

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6119

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53293

Other (OTH)

AF:

0.00

AC:

AN:

1527

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 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000107

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 specified (3)

Cardiovascular phenotype (2)

not provided (2)

GLA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

CardioboostCm

Uncertain

0.89

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.8

PhyloP100

7.9

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.80

MutPred

0.96

Loss of ubiquitination at K67 (P = 0.1)

MVP

0.98

MPC

1.7

ClinPred

0.29

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.99

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.90

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.44

Position offset: -3

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

Publications

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rs104894833

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over