X-101397655-C-T

Variant names:

• chrX-101397655-C-T
• rs35019768
• ENST00000409170.3:c.300+2198C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000409170.3(RPL36A-HNRNPH2):​c.300+2198C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 485,685 control chromosomes in the GnomAD database, including 2,940 homozygotes. There are 22,557 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (678 hom., 3923 hem., cov: 22)
  • Exomes 𝑓: 0.13 (2262 hom. 18634 hem.)
• Consequence: RPL36A-HNRNPH2 ENST00000409170.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.467
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-101397655-C-T is Benign according to our data. Variant chrX-101397655-C-T is described in ClinVar as [Benign]. Clinvar id is 1241572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.*154G>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+2198C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4
GLA	ENST00000218516.4	c.*154G>A		downstream_gene_variant		1	NM_000169.3	ENSP00000218516.4

Frequencies

GnomAD3 genomes AF: 0.126 AC: 13881 AN: 110027 Hom.: 678 Cov.: 22

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0869

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.141

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0997

GnomAD4 exome AF: 0.132 AC: 49606 AN: 375607 Hom.: 2262 AF XY: 0.145 AC XY: 18634 AN XY: 128773

African (AFR) AF: 0.152 AC: 1621 AN: 10631

American (AMR) AF: 0.129 AC: 2531 AN: 19569

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 1424 AN: 11329

East Asian (EAS) AF: 0.0793 AC: 1883 AN: 23737

South Asian (SAS) AF: 0.306 AC: 9408 AN: 30755

European-Finnish (FIN) AF: 0.0927 AC: 3212 AN: 34655

Middle Eastern (MID) AF: 0.0995 AC: 149 AN: 1497

European-Non Finnish (NFE) AF: 0.120 AC: 26601 AN: 222076

Other (OTH) AF: 0.130 AC: 2777 AN: 21358

GnomAD4 genome AF: 0.126 AC: 13887 AN: 110078 Hom.: 678 Cov.: 22 AF XY: 0.121 AC XY: 3923 AN XY: 32368

African (AFR) AF: 0.146 AC: 4411 AN: 30157

American (AMR) AF: 0.0969 AC: 1001 AN: 10334

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 348 AN: 2635

East Asian (EAS) AF: 0.0869 AC: 304 AN: 3498

South Asian (SAS) AF: 0.301 AC: 758 AN: 2522

European-Finnish (FIN) AF: 0.0840 AC: 484 AN: 5760

Middle Eastern (MID) AF: 0.146 AC: 31 AN: 213

European-Non Finnish (NFE) AF: 0.120 AC: 6349 AN: 52782

Other (OTH) AF: 0.0998 AC: 150 AN: 1503

Alfa AF: 0.135 Hom.: 758

Bravo AF: 0.128

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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	-0.90
CADD	Benign	4.0
DANN	Benign	0.55
PhyloP100		0.47

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: rs35019768; hg19: chrX-100652643;