rs782756052

Positions:

• chrX-101397924-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM5 BP4_Moderate

The NM_000169.3(GLA):​c.1175G>C​(p.Arg392Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,097,078 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R392S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.233

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101397923-C-A is described in ClinVar as [Likely_pathogenic, drug_response]. Clinvar id is 217413.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12355518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.1175G>C	p.Arg392Thr	missense_variant	7/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+2467C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.1175G>C	p.Arg392Thr	missense_variant	7/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000273 AC: 5 AN: 183469 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67909

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: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1097078 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362452

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: 0.0000924

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function. 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. ClinVar contains an entry for this variant (Variation ID: 524212). This variant has not been reported in the literature in individuals affected with GLA-related conditions. This variant is present in population databases (rs782756052, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 392 of the GLA protein (p.Arg392Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
CardioboostCm	Benign	0.0098
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.86
DANN	Benign	0.69
DEOGEN2	Uncertain	0.70	D;.
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.47	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Pathogenic	2.1	D
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.22
Sift	Benign	0.57	T;.
Sift4G	Benign	0.58	T;.
Polyphen		0.0010	B;.
Vest4		0.058
MutPred		0.47		Loss of MoRF binding (P = 0.0364);.;
MVP		0.78
MPC		1.0
ClinPred		0.017	T
GERP RS		-7.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs782756052; hg19: chrX-100652912;