rs3027589

Variant names:

• chrX-101400598-T-C
• rs3027589
• NM_000169.3:c.639+68A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000169.3(GLA):​c.639+68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0493 in 615,286 control chromosomes in the GnomAD database, including 891 homozygotes. There are 10,075 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (280 hom., 1972 hem., cov: 22)
  • Exomes 𝑓: 0.046 (611 hom. 8103 hem.)
• Consequence: GLA NM_000169.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.129
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-101400598-T-C is Benign according to our data. Variant chrX-101400598-T-C is described in ClinVar as Benign. ClinVar VariationId is 1275736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.639+68A>G		intron	N/A	NP_000160.1
	GLA	NM_001406747.1		c.762+68A>G		intron	N/A	NP_001393676.1
	GLA	NM_001406748.1		c.639+68A>G		intron	N/A	NP_001393677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.639+68A>G		intron	N/A	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+5141T>C		intron	N/A	ENSP00000386655.4
	GLA	ENST00000675968.1		n.1642A>G		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 7193 AN: 110691 Hom.: 279 Cov.: 22

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0117

Gnomad AMR AF: 0.0882

Gnomad ASJ AF: 0.00874

Gnomad EAS AF: 0.0348

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.00761

Gnomad MID AF: 0.0298

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0688

GnomAD4 exome AF: 0.0459 AC: 23135 AN: 504540 Hom.: 611 AF XY: 0.0496 AC XY: 8103 AN XY: 163476

African (AFR) AF: 0.146 AC: 2195 AN: 15061

American (AMR) AF: 0.131 AC: 4012 AN: 30517

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 206 AN: 15153

East Asian (EAS) AF: 0.0479 AC: 1278 AN: 26660

South Asian (SAS) AF: 0.107 AC: 4377 AN: 40794

European-Finnish (FIN) AF: 0.00971 AC: 370 AN: 38117

Middle Eastern (MID) AF: 0.0471 AC: 132 AN: 2801

European-Non Finnish (NFE) AF: 0.0302 AC: 9352 AN: 309288

Other (OTH) AF: 0.0464 AC: 1213 AN: 26149

GnomAD4 genome AF: 0.0650 AC: 7204 AN: 110746 Hom.: 280 Cov.: 22 AF XY: 0.0598 AC XY: 1972 AN XY: 32988

African (AFR) AF: 0.141 AC: 4283 AN: 30326

American (AMR) AF: 0.0879 AC: 914 AN: 10395

Ashkenazi Jewish (ASJ) AF: 0.00874 AC: 23 AN: 2631

East Asian (EAS) AF: 0.0350 AC: 122 AN: 3490

South Asian (SAS) AF: 0.109 AC: 285 AN: 2608

European-Finnish (FIN) AF: 0.00761 AC: 45 AN: 5916

Middle Eastern (MID) AF: 0.0327 AC: 7 AN: 214

European-Non Finnish (NFE) AF: 0.0267 AC: 1414 AN: 52965

Other (OTH) AF: 0.0679 AC: 103 AN: 1517

Alfa AF: 0.0507 Hom.: 3258

Bravo AF: 0.0762

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.4
DANN	Benign	0.78
PhyloP100		0.13
Mutation Taster		=100/0	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: rs3027589; hg19: chrX-100655586;