Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_000169.3(GLA):c.613C>G(p.Pro205Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,177,925 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. P205L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 9.98

Publications

33 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: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000169.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101400691-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 288308.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, 0.97

PP5

Variant X-101400692-G-C is Pathogenic according to our data. Variant chrX-101400692-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1711995.

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.613C>G	p.Pro205Ala	missense	Exon 4 of 7	NP_000160.1
GLA	NM_001406747.1		c.736C>G	p.Pro246Ala	missense	Exon 5 of 8	NP_001393676.1
GLA	NM_001406748.1		c.613C>G	p.Pro205Ala	missense	Exon 4 of 6	NP_001393677.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLA	ENST00000218516.4	TSL:1 MANE Select	c.613C>G	p.Pro205Ala	missense	Exon 4 of 7	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+5235G>C		intron	N/A	ENSP00000386655.4
GLA	ENST00000649178.1		c.736C>G	p.Pro246Ala	missense	Exon 5 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111650

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.38e-7

AC:

AN:

1066275

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

337931

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25846

American (AMR)

AF:

0.00

AC:

AN:

35141

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19156

East Asian (EAS)

AF:

0.00

AC:

AN:

30070

South Asian (SAS)

AF:

0.00

AC:

AN:

53236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40475

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4066

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

813209

Other (OTH)

AF:

0.0000222

AC:

AN:

45076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00000896

AC:

AN:

111650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33834

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30680

American (AMR)

AF:

0.00

AC:

AN:

10466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.00

AC:

AN:

2680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5999

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53168

Other (OTH)

AF:

0.00

AC:

AN:

1508

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fabry disease (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.3

PhyloP100

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.82

MutPred

0.81

Loss of loop (P = 0.0512)

MVP

0.98

MPC

1.7

ClinPred

1.0

GERP RS

5.3

Varity_R

0.97

gMVP

0.99

Mutation Taster

=8/92

disease causing

(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

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

rs397515870

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over