rs869312155

Variant names:

• chrX-101398443-G-A
• rs869312155
• NM_000169.3:c.926C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-101398443-G-A
• chrX-101398443-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001406747.1(GLA):​c.1049C>T​(p.Ala350Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,839 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A350S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: GLA NM_001406747.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 1.04
• Publications: 3 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 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_001406747.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398444-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4087582.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406747.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.926C>T	p.Ala309Val	missense	Exon 6 of 7	NP_000160.1
	GLA	NM_001406747.1		c.1049C>T	p.Ala350Val	missense	Exon 7 of 8	NP_001393676.1
	GLA	NM_001406748.1		c.926C>T	p.Ala309Val	missense	Exon 6 of 6	NP_001393677.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.926C>T	p.Ala309Val	missense	Exon 6 of 7	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2986G>A		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.1049C>T	p.Ala350Val	missense	Exon 7 of 8	ENSP00000498186.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095839 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361259

African (AFR) AF: 0.00 AC: 0 AN: 26363

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54091

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839963

Other (OTH) AF: 0.0000217 AC: 1 AN: 45999

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	Fabry disease (5)
-	2	-	not provided (2)
-	-	-	Migalastat response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
CardioboostCm	Benign	0.082
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.30
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.46	P
Vest4		0.24
MutPred		0.44		Loss of helix (P = 0.0558)
MVP		0.93
MPC		0.74
ClinPred		0.31	T
GERP RS		3.0
Varity_R		0.66
gMVP		0.89
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs869312155; hg19: chrX-100653431; COSMIC: COSV54508720; COSMIC: COSV54508720;