rs28935490

Variant names:

• chrX-101398432-C-A
• rs28935490
• NM_000169.3:c.937G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-101398432-C-A
• chrX-101398432-C-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000169.3(GLA):​c.937G>T​(p.Asp313Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,207,947 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,531 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D313N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., 104 hem., cov: 23)
  • Exomes 𝑓: 0.0038 (9 hom. 1427 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts U:5 B:20 O:3
• Conservation: PhyloP100: 0.136
• Publications: 176 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000169.3
• 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=0.021395475).
• BP6: Variant X-101398432-C-A is Benign according to our data. Variant chrX-101398432-C-A is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 10738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00314 (350/111368) while in subpopulation NFE AF = 0.00528 (280/53077). AF 95% confidence interval is 0.00477. There are 1 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 104 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.937G>T	p.Asp313Tyr	missense	Exon 6 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.1060G>T	p.Asp354Tyr	missense	Exon 7 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.937G>T	p.Asp313Tyr	missense	Exon 6 of 6	NP_001393677.1	A0A6Q8PHD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.937G>T	p.Asp313Tyr	missense	Exon 6 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2975C>A		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.1060G>T	p.Asp354Tyr	missense	Exon 7 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 350 AN: 111314 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00643

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.000505

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00527

Gnomad OTH AF: 0.00401

GnomAD2 exomes AF: 0.00303 AC: 556 AN: 183499 AF XY: 0.00352

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00681

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000625

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00419

GnomAD4 exome AF: 0.00384 AC: 4215 AN: 1096579 Hom.: 9 Cov.: 30 AF XY: 0.00394 AC XY: 1427 AN XY: 361981

African (AFR) AF: 0.000455 AC: 12 AN: 26378

American (AMR) AF: 0.00205 AC: 72 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00624 AC: 121 AN: 19378

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

South Asian (SAS) AF: 0.00327 AC: 177 AN: 54104

European-Finnish (FIN) AF: 0.000790 AC: 32 AN: 40531

Middle Eastern (MID) AF: 0.00437 AC: 18 AN: 4116

European-Non Finnish (NFE) AF: 0.00432 AC: 3632 AN: 840632

Other (OTH) AF: 0.00328 AC: 151 AN: 46035

GnomAD4 genome AF: 0.00314 AC: 350 AN: 111368 Hom.: 1 Cov.: 23 AF XY: 0.00310 AC XY: 104 AN XY: 33580

African (AFR) AF: 0.000717 AC: 22 AN: 30679

American (AMR) AF: 0.00153 AC: 16 AN: 10474

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 17 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.00230 AC: 6 AN: 2606

European-Finnish (FIN) AF: 0.000505 AC: 3 AN: 5946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.00528 AC: 280 AN: 53077

Other (OTH) AF: 0.00396 AC: 6 AN: 1515

Alfa AF: 0.00432 Hom.: 242

Bravo AF: 0.00285

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00554 AC: 16

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00431 AC: 29

ExAC AF: 0.00333 AC: 404

EpiCase AF: 0.00469

EpiControl AF: 0.00504

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	7	Fabry disease (11)
-	1	4	not provided (7)
-	-	3	Hypertrophic cardiomyopathy (3)
-	-	3	not specified (3)
-	1	1	Cardiovascular phenotype (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Sudden unexplained death (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.021	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.14
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.24
MVP		0.99
MPC		1.9
ClinPred		0.025	T
GERP RS		-5.0
Varity_R		0.86
gMVP		0.99
Mutation Taster		=57/43	polymorphism (auto)

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: rs28935490; hg19: chrX-100653420; COSMIC: COSV54510729; COSMIC: COSV54510729;