X-101398962-T-C

Variant names:

• chrX-101398962-T-C
• rs2071397
• NM_000169.3:c.640-16A>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.640-16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,180,033 control chromosomes in the GnomAD database, including 7,341 homozygotes. There are 50,881 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.13 (682 hom., 4319 hem., cov: 23)
  • Exomes 𝑓: 0.13 (6659 hom. 46562 hem.)
• Consequence: GLA NM_000169.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.649
• Publications: 25 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-101398962-T-C is Benign according to our data. Variant chrX-101398962-T-C is described in ClinVar as Benign. ClinVar VariationId is 92559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.291 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.640-16A>G		intron	N/A	NP_000160.1	P06280
	GLA	NM_001406747.1		c.763-16A>G		intron	N/A	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.640-16A>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.640-16A>G		intron	N/A	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+3505T>C		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.763-16A>G		intron	N/A	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.128 AC: 14288 AN: 111891 Hom.: 682 Cov.: 23

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0998

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.0871

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.0901

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.141 AC: 25883 AN: 183214 AF XY: 0.148

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0849

Gnomad FIN exome AF: 0.0923

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.131 AC: 139866 AN: 1068089 Hom.: 6659 Cov.: 28 AF XY: 0.138 AC XY: 46562 AN XY: 338483

African (AFR) AF: 0.152 AC: 3931 AN: 25805

American (AMR) AF: 0.131 AC: 4611 AN: 35177

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 2474 AN: 19185

East Asian (EAS) AF: 0.0815 AC: 2451 AN: 30092

South Asian (SAS) AF: 0.307 AC: 16385 AN: 53373

European-Finnish (FIN) AF: 0.0933 AC: 3779 AN: 40485

Middle Eastern (MID) AF: 0.101 AC: 304 AN: 3016

European-Non Finnish (NFE) AF: 0.122 AC: 99784 AN: 815876

Other (OTH) AF: 0.136 AC: 6147 AN: 45080

GnomAD4 genome AF: 0.128 AC: 14297 AN: 111944 Hom.: 682 Cov.: 23 AF XY: 0.126 AC XY: 4319 AN XY: 34144

African (AFR) AF: 0.148 AC: 4548 AN: 30821

American (AMR) AF: 0.0998 AC: 1052 AN: 10546

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 353 AN: 2645

East Asian (EAS) AF: 0.0868 AC: 310 AN: 3571

South Asian (SAS) AF: 0.309 AC: 829 AN: 2686

European-Finnish (FIN) AF: 0.0901 AC: 548 AN: 6079

Middle Eastern (MID) AF: 0.144 AC: 31 AN: 216

European-Non Finnish (NFE) AF: 0.121 AC: 6416 AN: 53175

Other (OTH) AF: 0.103 AC: 158 AN: 1528

Alfa AF: 0.133 Hom.: 1132

Bravo AF: 0.129

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Fabry disease (3)
-	-	3	not provided (3)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.061
DANN	Benign	0.36
PhyloP100		-0.65
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2071397; hg19: chrX-100653950; COSMIC: COSV54509030; COSMIC: COSV54509030;