rs397515869

chrX-101397946-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000169.3(GLA):c.1153A>G(p.Thr385Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,210,267 control chromosomes in the GnomAD database, including 1 homozygotes. There are 159 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T385I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00024 (1 hom. 148 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.37

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 -18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000169.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.012772888).
• BP6: Variant X-101397946-T-C is Benign according to our data. Variant chrX-101397946-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 42452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101397946-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000142 (16/112585) while in subpopulation SAS AF= 0.00587 (16/2726). AF 95% confidence interval is 0.00368. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.1153A>G	p.Thr385Ala	missense_variant	7/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+2489T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.1153A>G	p.Thr385Ala	missense_variant	7/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.000142 AC: 16 AN: 112532 Hom.: 0 Cov.: 23 AF XY: 0.000317 AC XY: 11 AN XY: 34686

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: 0.00585

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000556 AC: 102 AN: 183479 Hom.: 0 AF XY: 0.000898 AC XY: 61 AN XY: 67915

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: 0.00524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000240 AC: 263 AN: 1097682 Hom.: 1 Cov.: 30 AF XY: 0.000408 AC XY: 148 AN XY: 363042

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: 0.00454

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000142 AC: 16 AN: 112585 Hom.: 0 Cov.: 23 AF XY: 0.000317 AC XY: 11 AN XY: 34749

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00587

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000733 AC: 89

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2015	p.Thr385Ala in exon 7 of GLA: This variant is not expected to be disease causing on its own because it has been identified in 0.5% (53/10122; including 36 males ) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs397515869). Furthermore, it has been identified by our laboratory in 2 adults (1 male, 1 female) with DCM and did not segregate with disease in either family. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2016	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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Benign	0.0060
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	20
Dann	Benign	0.84
DEOGEN2	Uncertain	0.77	D;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;.
REVEL	Uncertain	0.61
Sift	Benign	0.27	T;.
Sift4G	Benign	0.74	T;.
Polyphen		0.71	P;.
Vest4		0.075
MutPred		0.45		Gain of helix (P = 0.132);.;
MVP		0.98
MPC		0.71
ClinPred		0.053	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515869; hg19: chrX-100652934;