rs200096940

Positions:

• chrX-101400660-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000169.3(GLA):​c.639+6A>C variant causes a splice donor 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. 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_donor_region, intron
• Scores: Splicing: ADA: 0.0007518
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.226

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 42457.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• BS2: High Hemizygotes in GnomAdExome4 at 9 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.639+6A>C		splice_donor_region_variant, intron_variant		ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2	c.300+5203T>G		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.639+6A>C		splice_donor_region_variant, intron_variant		1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110829 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33061

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

GnomAD3 exomes AF: 0.0000281 AC: 5 AN: 177659 Hom.: 0 AF XY: 0.0000638 AC XY: 4 AN XY: 62705

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000248

Gnomad4 NFE exome AF: 0.0000269

Gnomad4 OTH exome AF: 0.0000486

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change falls in intron 4 of the GLA gene. It does not directly change the encoded amino acid sequence of the GLA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200096940, gnomAD 0.006%). This variant has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 22805550). ClinVar contains an entry for this variant (Variation ID: 42457). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The c.639+6A>C variant in GLA has been reported in at least 1 individual with Fabry disease (PMID:22805550), and has been identified in 0.005% (1/15710) and 0.006% (4/78727) of European (Finnish) and European (non-Finnish) chromosomes, respectively, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200096940). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by the Laboratory for Molecular Medicine and as likely benign by GeneDx. (ID:42457). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One affected individuals with this variant had an alternative molecular basis for Fabry disease, suggesting that this variant may not be pathogenic. In summary, while the clinical significance of the c.639+6A>C variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS2, BP5, BP7, BP4, PM2_supporting (Richards 2015). -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 13, 2011	Variant classified as Uncertain Significance - Favor Benign. The 639+6A>C varian t (GLA) has not been previously reported but has been identified by our laborato ry in 1 individual with HCM who carried another possibly disease causing variant in the MYBPC3 gene. This variant occurs in the 5' splice site consensus sequenc e, but not in the invariant +1 or +2 positions. Computational tools do not predi ct an impact on splicing, though their accuracy is unknown. This variant is less likely disease causing but additional information is needed to confirm this. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs200096940; hg19: chrX-100655648;