rs2071226

Variant names:

• chrX-101407693-T-C
• rs2071226
• NM_000169.3:c.194+17A>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.194+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,188,364 control chromosomes in the GnomAD database, including 231 homozygotes. There are 1,864 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (28 hom., 190 hem., cov: 24)
  • Exomes 𝑓: 0.0048 (203 hom. 1674 hem.)
• Consequence: GLA NM_000169.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0110
• Publications: 4 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=-0.73).
• BP6: Variant X-101407693-T-C is Benign according to our data. Variant chrX-101407693-T-C is described in ClinVar as Benign. ClinVar VariationId is 193058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.194+17A>G		intron	N/A	NP_000160.1	P06280
	GLA	NM_001406747.1		c.194+17A>G		intron	N/A	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.194+17A>G		intron	N/A	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.194+17A>G		intron	N/A	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-4243T>C		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.194+17A>G		intron	N/A	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 566 AN: 110784 Hom.: 28 Cov.: 24

Gnomad AFR AF: 0.000132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00391

Gnomad ASJ AF: 0.000380

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.00531

Gnomad FIN AF: 0.00645

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00470

GnomAD2 exomes AF: 0.0109 AC: 1992 AN: 182637 AF XY: 0.0100

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.00581

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00475 AC: 5121 AN: 1077524 Hom.: 203 Cov.: 29 AF XY: 0.00485 AC XY: 1674 AN XY: 345174

African (AFR) AF: 0.000192 AC: 5 AN: 25998

American (AMR) AF: 0.000313 AC: 11 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.000260 AC: 5 AN: 19254

East Asian (EAS) AF: 0.131 AC: 3956 AN: 30111

South Asian (SAS) AF: 0.00464 AC: 249 AN: 53670

European-Finnish (FIN) AF: 0.00641 AC: 260 AN: 40531

Middle Eastern (MID) AF: 0.00122 AC: 5 AN: 4082

European-Non Finnish (NFE) AF: 0.000267 AC: 220 AN: 823260

Other (OTH) AF: 0.00903 AC: 410 AN: 45424

GnomAD4 genome AF: 0.00512 AC: 567 AN: 110840 Hom.: 28 Cov.: 24 AF XY: 0.00572 AC XY: 190 AN XY: 33216

African (AFR) AF: 0.000131 AC: 4 AN: 30442

American (AMR) AF: 0.00391 AC: 41 AN: 10499

Ashkenazi Jewish (ASJ) AF: 0.000380 AC: 1 AN: 2634

East Asian (EAS) AF: 0.125 AC: 438 AN: 3505

South Asian (SAS) AF: 0.00571 AC: 15 AN: 2627

European-Finnish (FIN) AF: 0.00645 AC: 38 AN: 5894

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.000398 AC: 21 AN: 52830

Other (OTH) AF: 0.00531 AC: 8 AN: 1507

Alfa AF: 0.00165 Hom.: 68

Bravo AF: 0.00619

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Fabry disease (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		-0.011
PromoterAI		-0.058	Neutral
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: rs2071226; hg19: chrX-100662681; COSMIC: COSV54509725; COSMIC: COSV54509725;