rs200096940

Variant names:

• chrX-101400660-T-G
• rs200096940
• NM_000169.3:c.639+6A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-101400660-T-G
• chrX-101400660-T-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000169.3(GLA):​c.639+6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 948,272 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000024 (0 hom. 9 hem.)
• Consequence: GLA NM_000169.3 splice_region, intron
• Scores: Splicing: ADA: 0.0007518
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.226
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant X-101400660-T-G is Benign according to our data. Variant chrX-101400660-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42457.
• BS2: High Hemizygotes in GnomAdExome4 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.639+6A>C		splice_region intron	N/A	NP_000160.1	P06280
	GLA	NM_001406747.1		c.762+6A>C		splice_region intron	N/A	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.639+6A>C		splice_region 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.639+6A>C		splice_region intron	N/A	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+5203T>G		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.762+6A>C		splice_region intron	N/A	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110829 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000281 AC: 5 AN: 177659 AF XY: 0.0000638

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000637

Gnomad NFE exome AF: 0.0000508

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 23 AN: 948272 Hom.: 0 Cov.: 17 AF XY: 0.0000327 AC XY: 9 AN XY: 274820

African (AFR) AF: 0.00 AC: 0 AN: 23636

American (AMR) AF: 0.00 AC: 0 AN: 34921

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18398

East Asian (EAS) AF: 0.00 AC: 0 AN: 29520

South Asian (SAS) AF: 0.00 AC: 0 AN: 50579

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40325

Middle Eastern (MID) AF: 0.000261 AC: 1 AN: 3827

European-Non Finnish (NFE) AF: 0.0000269 AC: 19 AN: 705882

Other (OTH) AF: 0.0000486 AC: 2 AN: 41184

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	Fabry disease (6)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		0.23
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00075
dbscSNV1_RF	Benign	0.068
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: rs200096940; hg19: chrX-100655648;