X-101397776-C-T

Variant names:

• chrX-101397776-C-T
• rs782094147
• ENST00000409170.3:c.300+2319C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000409170.3(RPL36A-HNRNPH2):​c.300+2319C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000535 in 1,121,884 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000020 (0 hom. 1 hem.)
• Consequence: RPL36A-HNRNPH2 ENST00000409170.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0900
• Publications: 0 publications found

Genes affected

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]

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]

GLA Gene-Disease associations (from GenCC):

• Fabry disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-101397776-C-T is Benign according to our data. Variant chrX-101397776-C-T is described in ClinVar as [Benign]. Clinvar id is 1268269.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.*33G>A		downstream_gene_variant		ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2319C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4
GLA	ENST00000218516.4	c.*33G>A		downstream_gene_variant		1	NM_000169.3	ENSP00000218516.4

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112550 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000129

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000554 AC: 1 AN: 180414 AF XY: 0.00

Gnomad AFR exome AF: 0.0000766

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000198 AC: 2 AN: 1009280 Hom.: 0 Cov.: 21 AF XY: 0.00000332 AC XY: 1 AN XY: 300900

African (AFR) AF: 0.0000404 AC: 1 AN: 24732

American (AMR) AF: 0.00 AC: 0 AN: 35087

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18822

East Asian (EAS) AF: 0.00 AC: 0 AN: 29857

South Asian (SAS) AF: 0.00 AC: 0 AN: 52239

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40429

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3353

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 761662

Other (OTH) AF: 0.00 AC: 0 AN: 43099

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112604 Hom.: 0 Cov.: 24 AF XY: 0.0000287 AC XY: 1 AN XY: 34790

African (AFR) AF: 0.000129 AC: 4 AN: 31040

American (AMR) AF: 0.00 AC: 0 AN: 10635

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2761

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6145

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53341

Other (OTH) AF: 0.00 AC: 0 AN: 1531

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.54
DANN	Benign	0.19
PhyloP100		-0.090

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

Other links and lift over

dbSNP: rs782094147; hg19: chrX-100652764;