X-101412559-GT-G

Variant names:

• chrX-101412559-GT-G
• rs1555988404
• NM_019597.5:c.573delT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_019597.5(HNRNPH2):​c.573delT​(p.Arg192GlufsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HNRNPH2 NM_019597.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.94
• Publications: 0 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101412559-GT-G is Pathogenic according to our data. Variant chrX-101412559-GT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 451161.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019597.5. 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
	HNRNPH2	NM_019597.5	MANE Select	c.573delT	p.Arg192GlufsTer40	frameshift	Exon 2 of 2	NP_062543.1	A0A384MDT2
	HNRNPH2	NM_001032393.3		c.573delT	p.Arg192GlufsTer40	frameshift	Exon 2 of 2	NP_001027565.1	P55795
	RPL36A-HNRNPH2	NM_001199973.2		c.*569delT		3_prime_UTR	Exon 5 of 5	NP_001186902.2	H7BZ11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPH2	ENST00000316594.6	TSL:1 MANE Select	c.573delT	p.Arg192GlufsTer40	frameshift	Exon 2 of 2	ENSP00000361927.2	P55795
	HNRNPH2	ENST00000867410.1		c.573delT	p.Arg192GlufsTer40	frameshift	Exon 2 of 2	ENSP00000537469.1
	HNRNPH2	ENST00000867411.1		c.573delT	p.Arg192GlufsTer40	frameshift	Exon 2 of 2	ENSP00000537470.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

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: rs1555988404; hg19: chrX-100667547;