X-101412073-C-T

Variant names:

• chrX-101412073-C-T
• rs1555988314
• NM_019597.5:c.85C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_019597.5(HNRNPH2):​c.85C>T​(p.Arg29Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: HNRNPH2 NM_019597.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.15
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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-101412073-C-T is Pathogenic according to our data. Variant chrX-101412073-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 807430.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.85C>T	p.Arg29Cys	missense	Exon 2 of 2	NP_062543.1	A0A384MDT2
	HNRNPH2	NM_001032393.3		c.85C>T	p.Arg29Cys	missense	Exon 2 of 2	NP_001027565.1	P55795
	RPL36A-HNRNPH2	NM_001199973.2		c.*81C>T		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.85C>T	p.Arg29Cys	missense	Exon 2 of 2	ENSP00000361927.2	P55795
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.*81C>T		3_prime_UTR	Exon 5 of 5	ENSP00000386655.4	H7BZ11
	HNRNPH2	ENST00000867410.1		c.85C>T	p.Arg29Cys	missense	Exon 2 of 2	ENSP00000537469.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183449 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097855 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363215

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841778

Other (OTH) AF: 0.00 AC: 0 AN: 46089

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, X-linked, syndromic, Bain type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.22
Sift	Benign	0.030	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.55		Gain of catalytic residue at D25 (P = 0.0796)
MVP		0.82
MPC		2.7
ClinPred		0.84	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.88
Mutation Taster		=82/18	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: rs1555988314; hg19: chrX-100667061; COSMIC: COSV54508490; COSMIC: COSV54508490;