rs1554700678

Positions:

• chr9-83975466-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_031263.4(HNRNPK):​c.253G>A​(p.Glu85Lys) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPK NM_031263.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_031263.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HNRNPK. . Gene score misZ 3.9922 (greater than the threshold 3.09). Trascript score misZ 3.2967 (greater than threshold 3.09). GenCC has associacion of gene with Au-Kline syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome.
• PP5: Variant 9-83975466-C-T is Pathogenic according to our data. Variant chr9-83975466-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 452520.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=4, Uncertain_significance=2}. Variant chr9-83975466-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPK	NM_031263.4	c.253G>A	p.Glu85Lys	missense_variant	6/17	ENST00000376263.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPK	ENST00000376263.8	c.253G>A	p.Glu85Lys	missense_variant	6/17	1	NM_031263.4	A1
HNRNPK-AS1	ENST00000448389.1	n.79C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Au-Kline syndrome Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	The Genetics Institute, Rambam Health Care Campus	Apr 01, 2018	This sequence change replaces Glutamic acid with Lysine at codon 85 of the HNRNPK protein p.(Glu85Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (gmomAD, dbSNP,). This variant was found in an individual with clinical symptomes compatible with Au-Kline syndrome (MIM:616580 ), de novo inheritance was confirmed. ClinVar contains an entry for this variant (Variation ID: 452520). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 03, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.29; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as likely pathogenic and uncertain significance for HNRNPK -related disorder (ClinVar ID: VCV000452520). Threrefore, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33057194, 35982159, 36130591, 33874999) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	HNRNPK: PS2, PM2, PS4:Moderate, PP2 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2018

- -

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	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;.;T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;D;.;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.055	T;T;T;T;.
Polyphen		0.0060	B;B;B;B;.
Vest4		0.81
MutPred		0.48		Gain of ubiquitination at E85 (P = 0.0101);Gain of ubiquitination at E85 (P = 0.0101);Gain of ubiquitination at E85 (P = 0.0101);Gain of ubiquitination at E85 (P = 0.0101);Gain of ubiquitination at E85 (P = 0.0101);
MVP		0.76
MPC		2.1
ClinPred		0.94	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.53
gMVP		0.98

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

Other links and lift over

dbSNP: rs1554700678; hg19: chr9-86590381; COSMIC: COSV61091028; COSMIC: COSV61091028;