chrX-101412605-G-A

Variant names:

• chrX-101412605-G-A
• rs886039764
• NM_019597.5:c.617G>A

Variant summary

Our verdict is Pathogenic. The variant received 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:15
• Conservation: PhyloP100: 8.04
• Publications: 12 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 225760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.6248 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to 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 Pathogenic. ClinVar VariationId is 225761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.617G>A	p.Arg206Gln	missense	Exon 2 of 2	NP_062543.1	A0A384MDT2
	HNRNPH2	NM_001032393.3		c.617G>A	p.Arg206Gln	missense	Exon 2 of 2	NP_001027565.1	P55795
	RPL36A-HNRNPH2	NM_001199973.2		c.*613G>A		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.617G>A	p.Arg206Gln	missense	Exon 2 of 2	ENSP00000361927.2	P55795
	HNRNPH2	ENST00000867410.1		c.617G>A	p.Arg206Gln	missense	Exon 2 of 2	ENSP00000537469.1
	HNRNPH2	ENST00000867411.1		c.617G>A	p.Arg206Gln	missense	Exon 2 of 2	ENSP00000537470.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Intellectual disability, X-linked, syndromic, Bain type (11)
3	-	-	not provided (3)
1	-	-	HNRNPH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		8.0
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
Mutation Taster		=22/78	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: rs886039764; hg19: chrX-100667593; COSMIC: COSV54508547; COSMIC: COSV54508547;