rs186392986

Variant names:

• chrX-101397753-A-C
• rs186392986
• ENST00000409170.3:c.300+2296A>C

Variant summary

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

The NM_001199973.2(RPL36A-HNRNPH2):​c.300+2296A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 1,051,302 control chromosomes in the GnomAD database, including 1 homozygotes. There are 158 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 0.00022 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00060 (1 hom. 153 hem.)
• Consequence: RPL36A-HNRNPH2 NM_001199973.2 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.07
• 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, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-101397753-A-C is Benign according to our data. Variant chrX-101397753-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3048387.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199973.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL36A-HNRNPH2	NM_001199973.2		c.300+2296A>C		intron	N/A	NP_001186902.2	H7BZ11
	RPL36A-HNRNPH2	NM_001199974.2		c.177+5931A>C		intron	N/A	NP_001186903.2	H0Y3V9
	GLA	NM_000169.3	MANE Select	c.*56T>G		downstream_gene	N/A	NP_000160.1	P06280

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2296A>C		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000710365.1		c.*56T>G		3_prime_UTR	Exon 8 of 8	ENSP00000518234.1	A0AA34QW02
	RPL36A-HNRNPH2	ENST00000409338.5	TSL:4	c.177+5931A>C		intron	N/A	ENSP00000386974.2	H0Y3V9

Frequencies

GnomAD3 genomes AF: 0.000222 AC: 25 AN: 112752 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

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: 0.000375

Gnomad OTH AF: 0.000659

GnomAD4 exome AF: 0.000601 AC: 564 AN: 938496 Hom.: 1 Cov.: 17 AF XY: 0.000569 AC XY: 153 AN XY: 268802

African (AFR) AF: 0.0000428 AC: 1 AN: 23341

American (AMR) AF: 0.000372 AC: 13 AN: 34941

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18363

East Asian (EAS) AF: 0.00 AC: 0 AN: 29483

South Asian (SAS) AF: 0.00 AC: 0 AN: 50538

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2904

European-Non Finnish (NFE) AF: 0.000762 AC: 532 AN: 697894

Other (OTH) AF: 0.000417 AC: 17 AN: 40752

GnomAD4 genome AF: 0.000222 AC: 25 AN: 112806 Hom.: 0 Cov.: 23 AF XY: 0.000143 AC XY: 5 AN XY: 34976

African (AFR) AF: 0.0000642 AC: 2 AN: 31129

American (AMR) AF: 0.000188 AC: 2 AN: 10664

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6200

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

European-Non Finnish (NFE) AF: 0.000375 AC: 20 AN: 53348

Other (OTH) AF: 0.000651 AC: 1 AN: 1536

Alfa AF: 0.000216 Hom.: 1

Bravo AF: 0.000242

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GLA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.6
DANN	Benign	0.80
PhyloP100		1.1

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: rs186392986; hg19: chrX-100652741;