NM_000169.3:c.640-854_640-853delAG

Variant names:

• chrX-101399798-GCT-G
• rs201655854
• NM_000169.3:c.640-854_640-853delAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000169.3(GLA):​c.640-854_640-853delAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 111,616 control chromosomes in the GnomAD database, including 9 homozygotes. There are 383 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (9 hom., 383 hem., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GLA NM_000169.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.567
• Publications: 0 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 -16 ACMG points.

• BP6: Variant X-101399798-GCT-G is Benign according to our data. Variant chrX-101399798-GCT-G is described in ClinVar as Benign. ClinVar VariationId is 42458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0118 (1312/111616) while in subpopulation SAS AF = 0.0424 (113/2666). AF 95% confidence interval is 0.036. There are 9 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.640-854_640-853delAG		intron	N/A	NP_000160.1
	GLA	NM_001406747.1		c.763-854_763-853delAG		intron	N/A	NP_001393676.1
	GLA	NM_001406748.1		c.640-854_640-853delAG		intron	N/A	NP_001393677.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.640-854_640-853delAG		intron	N/A	ENSP00000218516.4
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+4344_300+4345delCT		intron	N/A	ENSP00000386655.4
	GLA	ENST00000649178.1		c.763-854_763-853delAG		intron	N/A	ENSP00000498186.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1311 AN: 111560 Hom.: 9 Cov.: 22

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.0102

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00448

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.00629

Gnomad MID AF: 0.00855

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0207

GnomAD2 exomes AF: 0.00 AC: 0 AN: 10

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 24 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 21

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0118 AC: 1312 AN: 111616 Hom.: 9 Cov.: 22 AF XY: 0.0113 AC XY: 383 AN XY: 33862

African (AFR) AF: 0.00264 AC: 81 AN: 30711

American (AMR) AF: 0.0108 AC: 113 AN: 10481

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2647

East Asian (EAS) AF: 0.00449 AC: 16 AN: 3561

South Asian (SAS) AF: 0.0424 AC: 113 AN: 2666

European-Finnish (FIN) AF: 0.00629 AC: 38 AN: 6037

Middle Eastern (MID) AF: 0.00939 AC: 2 AN: 213

European-Non Finnish (NFE) AF: 0.0171 AC: 906 AN: 53103

Other (OTH) AF: 0.0205 AC: 31 AN: 1514

Alfa AF: 0.0155 Hom.: 88

Bravo AF: 0.0110

Asia WGS AF: 0.0360 AC: 90 AN: 2522

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Fabry disease (2)
-	-	1	Cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs201655854; hg19: chrX-100654786;