Genetic Variant HNRNPK:c.-110G>A (chr9-83980155-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_031263.4(HNRNPK):c.-110G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 152,386 control chromosomes in the GnomAD database, including 7,561 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7550 hom., cov: 33)

Exomes 𝑓: 0.30 ( 11 hom. )

Consequence

HNRNPK
NM_031263.4 splice_region

Scores

Splicing: ADA: 0.0001644

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.171

Publications

20 publications found

Variant links:

Genes affected

HNRNPK (HGNC:5044): (heterogeneous nuclear ribonucleoprotein K) 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 is located in the nucleoplasm and has three repeats of KH domains that binds to RNAs. It is distinct among other hnRNP proteins in its binding preference; it binds tenaciously to poly(C). This protein is also thought to have a role during cell cycle progession. Several alternatively spliced transcript variants have been described for this gene, however, not all of them are fully characterized. [provided by RefSeq, Jul 2008]

HNRNPK links:

RMI1 (HGNC:25764): (RecQ mediated genome instability 1) Predicted to enable nucleotide binding activity. Predicted to be involved in double-strand break repair via homologous recombination and resolution of meiotic recombination intermediates. Predicted to act upstream of or within glucose homeostasis; reduction of food intake in response to dietary excess; and response to glucose. Located in nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

RMI1 links:

ENSG00000309273 (HGNC:):

ENSG00000309273 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPK	NM_031263.4 link	c.-110G>A		splice_region_variant	Exon 1 of 17	ENST00000376263.8	NP_112553.1	P61978-2
HNRNPK	NM_031263.4 link	c.-110G>A		5_prime_UTR_variant	Exon 1 of 17	ENST00000376263.8	NP_112553.1	P61978-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPK	ENST00000376263.8 link	c.-110G>A		splice_region_variant	Exon 1 of 17	1	NM_031263.4	ENSP00000365439.3		P61978-2
HNRNPK	ENST00000376263.8 link	c.-110G>A		5_prime_UTR_variant	Exon 1 of 17	1	NM_031263.4	ENSP00000365439.3		P61978-2

Frequencies

GnomAD3 genomes

AF:

0.306

AC:

46455

AN:

151988

Hom.:

7546

Cov.:

show subpopulations

Gnomad AFR

AF:

0.420

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.268

Gnomad SAS

AF:

0.364

Gnomad FIN

AF:

0.255

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.309

GnomAD4 exome

AF:

0.299

AC:

AN:

278

Hom.:

Cov.:

AF XY:

0.278

AC XY:

AN XY:

212

show subpopulations

African (AFR)

AF:

0.833

AC:

AN:

American (AMR)

AF:

0.250

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

0.375

AC:

AN:

South Asian (SAS)

AF:

0.375

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.257

AC:

AN:

230

Other (OTH)

AF:

0.563

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.306

AC:

46495

AN:

152108

Hom.:

7550

Cov.:

AF XY:

0.307

AC XY:

22807

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.420

AC:

17430

AN:

41500

American (AMR)

AF:

0.216

AC:

3300

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

975

AN:

3470

East Asian (EAS)

AF:

0.268

AC:

1376

AN:

5142

South Asian (SAS)

AF:

0.365

AC:

1759

AN:

4822

European-Finnish (FIN)

AF:

0.255

AC:

2696

AN:

10588

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.266

AC:

18048

AN:

67970

Other (OTH)

AF:

0.312

AC:

659

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1657

3314

4972

6629

8286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.278

Hom.:

7299

Bravo

AF:

0.303

Asia WGS

AF:

0.313

AC:

1090

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

0.17

PromoterAI

0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=297/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over