rs1555987232

Variant names:

• chrX-101407902-A-G
• rs1555987232
• NM_000169.3:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-101407902-A-G
• chrX-101407902-A-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000169.3(GLA):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.51
• Publications: 1 publications found

Genes affected

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]

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]

HNRNPH2 (HGNC:5042): (heterogeneous nuclear ribonucleoprotein H2) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has three repeats of quasi-RRM domains that binds to RNAs. It is very similar to the family member HNRPH1. This gene is thought to be involved in Fabray disease and X-linked agammaglobulinemia phenotype. Alternative splicing results in multiple transcript variants encoding the same protein. Read-through transcription between this locus and the ribosomal protein L36a gene has been observed. [provided by RefSeq, Jan 2011]

HNRNPH2 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, X-linked, syndromic, Bain type

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 80 pathogenic variants. Next in-frame start position is after 42 codons. Genomic position: 101407780. Lost 0.096 part of the original CDS.
• PS1: Another start lost variant in NM_000169.3 (GLA) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101407902-A-G is Pathogenic according to our data. Variant chrX-101407902-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 495694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000169.3. 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
	GLA	NM_000169.3	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 6	NP_001393677.1	A0A6Q8PHD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-4034A>G		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Fabry disease (4)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.6	D
PhyloP100		1.5
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.15	B
Vest4		0.86
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0236)
MVP		1.0
ClinPred		0.89	D
GERP RS		4.0
PromoterAI		-0.28	Neutral
Varity_R		0.88
gMVP		0.96
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1555987232; hg19: chrX-100662890;