rs781838005

Variant names:

• chrX-101403941-C-G
• rs781838005
• NM_000169.3:c.239G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-101403941-C-G
• chrX-101403941-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PM1 PM2 PP2 PP3_Strong BP6_Moderate

The NM_000169.3(GLA):​c.239G>C​(p.Gly80Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 112,527 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G80D) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.90
• Publications: 5 publications found

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]

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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, 8 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.987
• BP6: Variant X-101403941-C-G is Benign according to our data. Variant chrX-101403941-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1199178.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.239G>C	p.Gly80Ala	missense_variant	Exon 2 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.239G>C	p.Gly80Ala	missense_variant	Exon 2 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.301-7995C>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112527 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000277

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

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112527 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34697

African (AFR) AF: 0.00 AC: 0 AN: 30997

American (AMR) AF: 0.00 AC: 0 AN: 10611

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.000277 AC: 1 AN: 3606

South Asian (SAS) AF: 0.00 AC: 0 AN: 2752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53302

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Benign:1

Jun 27, 2024

3billion

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
CardioboostCm	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.6	H;.
PhyloP100		7.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.89		Gain of catalytic residue at G80 (P = 0.0419);.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs781838005; hg19: chrX-100658929;