rs296885

Variant names:

• chr9-83969988-A-G
• rs296885
• NM_031263.4:c.1361+174T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031263.4(HNRNPK):​c.1361+174T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 646,340 control chromosomes in the GnomAD database, including 151,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (41476 hom., cov: 33)
  • Exomes 𝑓: 0.66 (110258 hom.)
• Consequence: HNRNPK NM_031263.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.709
• Publications: 6 publications found

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)

MIR7-1 (HGNC:31638): (microRNA 7-1) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-83969988-A-G is Benign according to our data. Variant chr9-83969988-A-G is described in ClinVar as Benign. ClinVar VariationId is 1222255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPK	NM_031263.4	MANE Select	c.1361+174T>C		intron	N/A	NP_112553.1	P61978-2
	HNRNPK	NM_002140.5		c.1361+174T>C		intron	N/A	NP_002131.2
	HNRNPK	NM_001318188.2		c.1361+174T>C		intron	N/A	NP_001305117.1	P61978-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPK	ENST00000376263.8	TSL:1 MANE Select	c.1361+174T>C		intron	N/A	ENSP00000365439.3	P61978-2
	HNRNPK	ENST00000376281.8	TSL:1	c.1361+174T>C		intron	N/A	ENSP00000365458.4	P61978-2
	HNRNPK	ENST00000360384.9	TSL:1	c.1361+174T>C		intron	N/A	ENSP00000353552.5	P61978-1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110188 AN: 152050 Hom.: 41406 Cov.: 33

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.697

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.691

GnomAD4 exome AF: 0.663 AC: 327795 AN: 494172 Hom.: 110258 Cov.: 5 AF XY: 0.662 AC XY: 176344 AN XY: 266338

African (AFR) AF: 0.931 AC: 12177 AN: 13082

American (AMR) AF: 0.494 AC: 10741 AN: 21736

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 10950 AN: 15838

East Asian (EAS) AF: 0.522 AC: 15935 AN: 30524

South Asian (SAS) AF: 0.657 AC: 34796 AN: 52936

European-Finnish (FIN) AF: 0.716 AC: 24463 AN: 34166

Middle Eastern (MID) AF: 0.675 AC: 1421 AN: 2106

European-Non Finnish (NFE) AF: 0.671 AC: 198691 AN: 296316

Other (OTH) AF: 0.678 AC: 18621 AN: 27468

GnomAD4 genome AF: 0.725 AC: 110313 AN: 152168 Hom.: 41476 Cov.: 33 AF XY: 0.722 AC XY: 53749 AN XY: 74402

African (AFR) AF: 0.929 AC: 38554 AN: 41522

American (AMR) AF: 0.572 AC: 8736 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 2418 AN: 3470

East Asian (EAS) AF: 0.518 AC: 2686 AN: 5182

South Asian (SAS) AF: 0.635 AC: 3064 AN: 4822

European-Finnish (FIN) AF: 0.709 AC: 7503 AN: 10584

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45146 AN: 67992

Other (OTH) AF: 0.693 AC: 1460 AN: 2106

Alfa AF: 0.683 Hom.: 18108

Bravo AF: 0.721

Asia WGS AF: 0.609 AC: 2116 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.4
DANN	Benign	0.79
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs296885; hg19: chr9-86584903;