X-101397714-T-C

Variant names:

• chrX-101397714-T-C
• rs782774060
• ENST00000409170.3:c.300+2257T>C

Variant summary

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

The ENST00000409170.3(RPL36A-HNRNPH2):​c.300+2257T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 778,622 control chromosomes in the GnomAD database, including 3 homozygotes. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., 57 hem., cov: 23)
  • Exomes 𝑓: 0.00025 (1 hom. 45 hem.)
• Consequence: RPL36A-HNRNPH2 ENST00000409170.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.115
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-101397714-T-C is Benign according to our data. Variant chrX-101397714-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3030728.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.*95A>G		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+2257T>C		intron_variant	Intron 4 of 4	4		ENSP00000386655.4
GLA	ENST00000218516.4	c.*95A>G		downstream_gene_variant		1	NM_000169.3	ENSP00000218516.4

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 113 AN: 112673 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

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: 0.000661

GnomAD4 exome AF: 0.000246 AC: 164 AN: 665893 Hom.: 1 AF XY: 0.000231 AC XY: 45 AN XY: 195187

African (AFR) AF: 0.00 AC: 0 AN: 17816

American (AMR) AF: 0.00475 AC: 157 AN: 33047

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15992

East Asian (EAS) AF: 0.00 AC: 0 AN: 27605

South Asian (SAS) AF: 0.00 AC: 0 AN: 43121

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39183

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 455377

Other (OTH) AF: 0.000221 AC: 7 AN: 31636

GnomAD4 genome AF: 0.00100 AC: 113 AN: 112729 Hom.: 2 Cov.: 23 AF XY: 0.00163 AC XY: 57 AN XY: 34879

African (AFR) AF: 0.0000322 AC: 1 AN: 31052

American (AMR) AF: 0.0104 AC: 111 AN: 10667

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3616

South Asian (SAS) AF: 0.00 AC: 0 AN: 2738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6191

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53375

Other (OTH) AF: 0.000652 AC: 1 AN: 1533

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GLA-related disorder Benign:1

May 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.63
PhyloP100		-0.12

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: rs782774060; hg19: chrX-100652702;