Genetic Variant NM_000169.3:c.1153A>G (chrX-101397946-T-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1PM5PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000169.3(GLA):c.1153A>G(p.Thr385Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,210,267 control chromosomes in the GnomAD database, including 1 homozygotes. There are 159 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T385P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.00024 ( 1 hom. 148 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.37

Publications

13 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000169.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101397946-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 4087650.Status of the report is criteria_provided_single_submitter, 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.012772888).

BP6

Variant X-101397946-T-C is Benign according to our data. Variant chrX-101397946-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000142 (16/112585) while in subpopulation SAS AF = 0.00587 (16/2726). AF 95% confidence interval is 0.00368. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 11 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	UniProt
GLA	NM_000169.3	MANE Select	c.1153A>G	p.Thr385Ala	missense	Exon 7 of 7	NP_000160.1	P06280
GLA	NM_001406747.1		c.1276A>G	p.Thr426Ala	missense	Exon 8 of 8	NP_001393676.1	A0A3B3IUC4
RPL36A-HNRNPH2	NM_001199973.2		c.300+2489T>C		intron	N/A	NP_001186902.2	H7BZ11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLA	ENST00000218516.4	TSL:1 MANE Select	c.1153A>G	p.Thr385Ala	missense	Exon 7 of 7	ENSP00000218516.4	P06280
RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2489T>C		intron	N/A	ENSP00000386655.4	H7BZ11
GLA	ENST00000649178.1		c.1276A>G	p.Thr426Ala	missense	Exon 8 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes

AF:

0.000142

AC:

AN:

112532

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:

0.00585

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000556

AC:

102

AN:

183479

AF XY:

0.000898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000240

AC:

263

AN:

1097682

Hom.:

Cov.:

AF XY:

0.000408

AC XY:

148

AN XY:

363042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26386

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00454

AC:

246

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841625

Other (OTH)

AF:

0.000282

AC:

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.000142

AC:

AN:

112585

Hom.:

Cov.:

AF XY:

0.000317

AC XY:

AN XY:

34749

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31049

American (AMR)

AF:

0.00

AC:

AN:

10641

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2662

East Asian (EAS)

AF:

0.00

AC:

AN:

3583

South Asian (SAS)

AF:

0.00587

AC:

AN:

2726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6191

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53287

Other (OTH)

AF:

0.00

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000215

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000733

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fabry disease (7)

not provided (3)

not specified (2)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

CardioboostCm

Benign

0.0060

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Uncertain

0.77

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.013

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PhyloP100

2.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.61

Sift

Benign

0.27

Sift4G

Benign

0.74

Polyphen

0.71

Vest4

0.075

MutPred

0.45

Gain of helix (P = 0.132)

MVP

0.98

MPC

0.71

ClinPred

0.053

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.44

gMVP

0.87

Mutation Taster

=46/54

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over