9-83971976-G-C

Position:

• chr9-83971976-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_031263.4(HNRNPK):​c.859C>G​(p.Arg287Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HNRNPK NM_031263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25

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 Uncertain_significance. Variant got 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39055377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPK	NM_031263.4	c.859C>G	p.Arg287Gly	missense_variant	11/17	ENST00000376263.8	NP_112553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPK	ENST00000376263.8	c.859C>G	p.Arg287Gly	missense_variant	11/17	1	NM_031263.4	ENSP00000365439	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455954 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	.;T;.;D;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.033	D;D;D;D;D
Sift4G	Benign	0.54	T;T;T;T;.
Polyphen		0.55	P;P;P;P;.
Vest4		0.70
MutPred		0.33		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);.;
MVP		0.90
MPC		1.6
ClinPred		0.85	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.21
gMVP		0.70

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: rs1554698878; hg19: chr9-86586891;