rs886039764

chrX-101412605-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_019597.5(HNRNPH2):c.617G>A(p.Arg206Gln) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HNRNPH2 NM_019597.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.04

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:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_019597.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101412604-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, HNRNPH2
• PP5: Variant X-101412605-G-A is Pathogenic according to our data. Variant chrX-101412605-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 225761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPH2	NM_019597.5	c.617G>A	p.Arg206Gln	missense_variant	2/2	ENST00000316594.6
RPL36A-HNRNPH2	NM_001199973.2	c.*613G>A		3_prime_UTR_variant	5/5
HNRNPH2	NM_001032393.3	c.617G>A	p.Arg206Gln	missense_variant	2/2
RPL36A-HNRNPH2	NM_001199974.2	c.*613G>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPH2	ENST00000316594.6	c.617G>A	p.Arg206Gln	missense_variant	2/2	1	NM_019597.5	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked, syndromic, Bain type Pathogenic:7

Likely pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Mar 16, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-03-16 and interpreted as Likely Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 22, 2020	PS2, PS4 – moderate, PM1, PM2, PP3 The HNRNPH2 c.617G>A variant is a single nucleotide change from a guanine to an adenine at position 617 which is predicted to alter the amino acid arginine at position 206 in the protein to glutamine. The variant is de novo (both maternity and paternity confirmed) in a patient with the disease and no family history (PS2). The variant is in dbSNP (rs886039764) but is absent from population databases (PM2). This variant has been previously reported as de novo in a female patient with developmental delay, intellectual disability, and hypotonia, (PMID: 27545675) and more recently in similarly affected males (PMID: 30887513) (PS4 – moderate). The variant is located in exon 2 and this position is a mutational hotspot with other de novo variants reported at this position (e.g. Arg206Trp PMID: 27545675, PMID: 31236915; Arg206Leu PMID: 31943778) (PM1). The variant has been reported in ClinVar as Pathogenic by another diagnostic laboratory (Variation ID 225761). Computational predictions support a deleterious effect on the gene or gene product (PP3). -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Mar 05, 2020	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Medical Genetics, University of Torino	Nov 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 20, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34907471, 27545675, 29938792, 31164858, 30887513, 31236915, 31943778, 33504798, 33728377, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	HNRNPH2: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

HNRNPH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2022

The HNRNPH2 c.617G>A variant is predicted to result in the amino acid substitution p.Arg206Gln. This variant has been previously reported as causative for X-linked HNRNPH2-related neurodevelopmental disorder (Bain et al. 2016. PubMed ID: 27545675; Harmsen et al. 2019. PubMed ID: 30887513; Patient 071 in Demos et al. 2019. PubMed ID: 31164858; Martin et al. 2021. PubMed ID: 33504798, Supplementary Data 2; Bain et al. 2021. PubMed ID: 33728377). An alternate nucleotide change affecting the same amino acid (c.616C>T, p.Arg206Trp) has also been reported in individuals with HNRNPH2-related neurodevelopmental disorder (see for example Jepsen et al. 2019. PubMed ID: 31236915; Bain et al. 2021. PubMed ID: 33728377). In addition, this variant is interpreted as pathogenic or likely pathogenic by multiple laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/225761/). We therefore classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0083	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.026	D
Polyphen		0.051	B
Vest4		0.81
MutPred		0.30		Loss of MoRF binding (P = 0.0284);
MVP		0.88
MPC		1.8
ClinPred		0.96	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039764; hg19: chrX-100667593; COSMIC: COSV54508547; COSMIC: COSV54508547;