rs863223403

Variant names:

• chr9-83975462-C-T
• rs863223403
• NM_031263.4:c.257G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_031263.4(HNRNPK):​c.257G>A​(p.Arg86His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPK NM_031263.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.54

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-AS1 (HGNC:56061): (HNRNPK antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the HNRNPK gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 3.9922 (above the threshold of 3.09). Trascript score misZ: 3.2967 (above the threshold of 3.09). GenCC associations: The gene is linked to Au-Kline syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-83975462-C-T is Pathogenic according to our data. Variant chr9-83975462-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-83975462-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPK	NM_031263.4	c.257G>A	p.Arg86His	missense_variant, splice_region_variant	Exon 6 of 17	ENST00000376263.8	NP_112553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPK	ENST00000376263.8	c.257G>A	p.Arg86His	missense_variant, splice_region_variant	Exon 6 of 17	1	NM_031263.4	ENSP00000365439.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Au-Kline syndrome Pathogenic:4 Other:1

Oct 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 07, 2018

Clinical Genetics Research Group, University of Calgary

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant is predicted to result in a missense variant (p.Arg86His) but has been shown to cause a splicing defect and decreased protein production. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	37
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;.;T;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	.;T;.;T;T
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	2.9	M;M;M;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;.
Polyphen		0.015	B;B;B;B;.
Vest4		0.78
MutPred		0.70		Loss of phosphorylation at S89 (P = 0.0739);Loss of phosphorylation at S89 (P = 0.0739);Loss of phosphorylation at S89 (P = 0.0739);Loss of phosphorylation at S89 (P = 0.0739);Loss of phosphorylation at S89 (P = 0.0739);
MVP		0.74
MPC		2.3
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.75
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223403; hg19: chr9-86590377;