X-101397814-G-A

Variant names:

• chrX-101397814-G-A
• rs1555984716
• NM_000169.3:c.1285C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_000169.3(GLA):​c.1285C>T​(p.Leu429Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000926 in 1,080,235 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.174
• Publications: 0 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_benign. The variant received -1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11173022).
• BP6: Variant X-101397814-G-A is Benign according to our data. Variant chrX-101397814-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3854129.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.1285C>T	p.Leu429Phe	missense_variant	Exon 7 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.1285C>T	p.Leu429Phe	missense_variant	Exon 7 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2357G>A		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182910 AF XY: 0.00

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.26e-7 AC: 1 AN: 1080235 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 347131

African (AFR) AF: 0.00 AC: 0 AN: 26082

American (AMR) AF: 0.00 AC: 0 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19273

East Asian (EAS) AF: 0.00 AC: 0 AN: 30136

South Asian (SAS) AF: 0.00 AC: 0 AN: 53743

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 825754

Other (OTH) AF: 0.00 AC: 0 AN: 45488

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Jan 29, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
CardioboostCm	Benign	0.085
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.9
DANN	Benign	0.83
DEOGEN2	Benign	0.17	T;.
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Pathogenic	1.9	D
MutationAssessor	Benign	0.0	N;.
PhyloP100		-0.17
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.10	N;.
REVEL	Benign	0.24
Sift	Benign	0.37	T;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.0010	B;.
Vest4		0.17
MutPred		0.40		Gain of methylation at K426 (P = 0.0745);.;
MVP		0.32
MPC		0.77
ClinPred		0.036	T
GERP RS		0.58
Varity_R		0.056
gMVP		0.65
Mutation Taster		=100/0	polymorphism

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: rs1555984716; hg19: chrX-100652802;