9-83970283-G-A

Variant names:

• chr9-83970283-G-A
• rs1348162749
• NM_031263.4:c.1240C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_031263.4(HNRNPK):​c.1240C>T​(p.Arg414Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPK NM_031263.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.53

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant 9-83970283-G-A is Pathogenic according to our data. Variant chr9-83970283-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1685880.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPK	NM_031263.4	c.1240C>T	p.Arg414Cys	missense_variant	Exon 16 of 17	ENST00000376263.8	NP_112553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPK	ENST00000376263.8	c.1240C>T	p.Arg414Cys	missense_variant	Exon 16 of 17	1	NM_031263.4	ENSP00000365439.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Au-Kline syndrome Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M;M;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.024	B;B;B;B
Vest4		0.78
MutPred		0.72		Loss of MoRF binding (P = 0.0146);Loss of MoRF binding (P = 0.0146);Loss of MoRF binding (P = 0.0146);Loss of MoRF binding (P = 0.0146);
MVP		0.87
MPC		1.4
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1348162749; hg19: chr9-86585198; COSMIC: COSV61088725; COSMIC: COSV61088725;