X-101397760-T-C

Variant names:

• chrX-101397760-T-C
• rs191249601
• ENST00000409170.3:c.300+2303T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000409170.3(RPL36A-HNRNPH2):​c.300+2303T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,073,728 control chromosomes in the GnomAD database, including 3 homozygotes. There are 141 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., 80 hem., cov: 23)
  • Exomes 𝑓: 0.00024 (3 hom. 61 hem.)
• Consequence: RPL36A-HNRNPH2 ENST00000409170.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.140
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-101397760-T-C is Benign according to our data. Variant chrX-101397760-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1187221.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 80 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.*49A>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+2303T>C		intron_variant	Intron 4 of 4	4		ENSP00000386655.4
GLA	ENST00000218516.4	c.*49A>G		downstream_gene_variant		1	NM_000169.3	ENSP00000218516.4

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 278 AN: 112591 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00739

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

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: 0.00329

GnomAD2 exomes AF: 0.000674 AC: 120 AN: 177962 AF XY: 0.000418

Gnomad AFR exome AF: 0.00823

Gnomad AMR exome AF: 0.000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.000245 AC: 235 AN: 961087 Hom.: 3 Cov.: 18 AF XY: 0.000219 AC XY: 61 AN XY: 278511

African (AFR) AF: 0.00739 AC: 176 AN: 23819

American (AMR) AF: 0.000828 AC: 29 AN: 35017

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18503

East Asian (EAS) AF: 0.00 AC: 0 AN: 29589

South Asian (SAS) AF: 0.00 AC: 0 AN: 51049

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40331

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3032

European-Non Finnish (NFE) AF: 0.00000696 AC: 5 AN: 718251

Other (OTH) AF: 0.000602 AC: 25 AN: 41496

GnomAD4 genome AF: 0.00247 AC: 278 AN: 112641 Hom.: 0 Cov.: 23 AF XY: 0.00230 AC XY: 80 AN XY: 34843

African (AFR) AF: 0.00737 AC: 229 AN: 31063

American (AMR) AF: 0.00412 AC: 44 AN: 10667

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3613

South Asian (SAS) AF: 0.00 AC: 0 AN: 2748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6155

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53306

Other (OTH) AF: 0.00325 AC: 5 AN: 1537

Alfa AF: 0.00177 Hom.: 10

Bravo AF: 0.00349

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 15, 2020

GeneDx

Significance: Likely 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	-0.87
CADD	Benign	0.61
DANN	Benign	0.41
PhyloP100		-0.14

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: rs191249601; hg19: chrX-100652748;