X-101412757-T-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2

The NM_019597.5(HNRNPH2):c.769T>A(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,208,274 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 131 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00035 ( 0 hom. 125 hem. )

Consequence

HNRNPH2
NM_019597.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.09

Variant links:

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]

HNRNPH2 links:

RPL36A-HNRNPH2 (HGNC:):

RPL36A-HNRNPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PP2

Missense variant where missense usually causes diseases, HNRNPH2

BP4

Computational evidence support a benign effect (MetaRNN=0.10954675).

BP6

Variant X-101412757-T-A is Benign according to our data. Variant chrX-101412757-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1049638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101412757-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000171 (19/111270) while in subpopulation NFE AF= 0.000359 (19/52952). AF 95% confidence interval is 0.000235. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HNRNPH2	NM_019597.5 linkuse as main transcript	c.769T>A	p.Ser257Thr	missense_variant	2/2	ENST00000316594.6
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.*765T>A		3_prime_UTR_variant	5/5
HNRNPH2	NM_001032393.3 linkuse as main transcript	c.769T>A	p.Ser257Thr	missense_variant	2/2
RPL36A-HNRNPH2	NM_001199974.2 linkuse as main transcript	c.*765T>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPH2	ENST00000316594.6 linkuse as main transcript	c.769T>A	p.Ser257Thr	missense_variant	2/2	1	NM_019597.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

111216

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

33436

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000359

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000169

AC:

AN:

183504

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

67938

show subpopulations

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 SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000293

Gnomad OTH exome

AF:

0.000441

GnomAD4 exome

AF:

0.000347

AC:

381

AN:

1097004

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

125

AN XY:

362370

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000554

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000403

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.000171

AC:

AN:

111270

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

33500

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000359

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	HNRNPH2: PP2, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The HNRNPH2 p.Ser257Thr variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs201300968) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 32 of 205159 chromosomes (11 hemizygous) at a frequency of 0.000156 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 5333 chromosomes (freq: 0.000375), European (non-Finnish) in 25 of 92650 chromosomes (freq: 0.00027) and South Asian in 5 of 19080 chromosomes (freq: 0.000262), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Ser257 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

HNRNPH2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.73

Cadd

Benign

Dann

Benign

0.86

DEOGEN2

Benign

0.21

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.51

M_CAP

Benign

0.0047

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.27

REVEL

Benign

0.11

Sift

Benign

0.56

Sift4G

Benign

0.44

Polyphen

0.0080

Vest4

0.16

MVP

0.60

MPC

1.4

ClinPred

0.027

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over