X-101412605-G-A

Position:

• chrX-101412605-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HNRNPH2 NM_019597.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• 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: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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HNRNPH2. . Gene score misZ 3.6248 (greater than the threshold 3.09). GenCC has associacion of gene with intellectual disability, X-linked, syndromic, Bain type.
• PP5: Variant X-101412605-G-A is Pathogenic according to our data. Variant chrX-101412605-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225761.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPH2	NM_019597.5	c.617G>A	p.Arg206Gln	missense_variant	2/2	ENST00000316594.6	NP_062543.1
HNRNPH2	NM_001032393.3	c.617G>A	p.Arg206Gln	missense_variant	2/2		NP_001027565.1
RPL36A-HNRNPH2	NM_001199973.2	c.*613G>A		3_prime_UTR_variant	5/5		NP_001186902.2
RPL36A-HNRNPH2	NM_001199974.2	c.*613G>A		3_prime_UTR_variant	4/4		NP_001186903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPH2	ENST00000316594.6	c.617G>A	p.Arg206Gln	missense_variant	2/2	1	NM_019597.5	ENSP00000361927.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked, syndromic, Bain type Pathogenic:10

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). -
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	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, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 13, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Apr 24, 2023	PS4, PM2, PM5, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 225761). This variant has been previously reported as causative for X-linked HNRNPH2-related neurodevelopmental disorder (PMID:34907471). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 02, 2023	The observed missense variant c.617G>A(p.Arg206Gln) in HNRNPH2 gene has been reported previously in individuals with developmental delay, intellectual disability, and hypotonia (Bain JM, et al., 2016, Jepsen WM, et al., 2019). A different amino acid change as a known pathogenic variant has been reported c.616C>T(p.Arg206Trp).The (p.Arg206Gln) variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/Pathogenic (multiple submissions). The amino acid Arginine at position 206 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen-Benign, SIFT-Tolerated and Mutation Taster-disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid p.Arg206Gln in HNRNPH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a suggested mechanism of disease in this gene (PMID:27545675) and is associated with intellectual developmental disorder, X-linked syndromic, Bain type (MIM#300986). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. De novo missense variants at this amino acid position have been reported many times in individuals affected with disease (ClinVar, PMID: 33728377). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times in ClinVar as pathogenic and is a repeatedly seen de novo variant in individuals (both male and female) presenting with intellectual disability, regression and growth issues (PMID: 27545675, 33728377, 32335897). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies demonstrate that this variant creates a defect in protein localisation (PMID:34907471). Accumulation of similar HNRNP proteins in the cytoplasm can lead to neurodegenerative conditions (PMID:27545675). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

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	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	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
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;