NM_198268.3:c.26C>T

Variant names:

• chr1-113940409-C-T
• rs371625292
• NM_198268.3:c.26C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_198268.3(HIPK1):​c.26C>T​(p.Ser9Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000883 in 1,608,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: HIPK1 NM_198268.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 1 publications found

Genes affected

HIPK1 (HGNC:19006): (homeodomain interacting protein kinase 1) The protein encoded by this gene belongs to the Ser/Thr family of protein kinases and HIPK subfamily. It phosphorylates homeodomain transcription factors and may also function as a co-repressor for homeodomain transcription factors. Alternative splicing results in four transcript variants encoding four distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198268.3. 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
	HIPK1	NM_198268.3	MANE Select	c.26C>T	p.Ser9Leu	missense	Exon 2 of 16	NP_938009.1	Q86Z02-1
	HIPK1	NM_001369806.1		c.26C>T	p.Ser9Leu	missense	Exon 2 of 16	NP_001356735.1	Q86Z02-1
	HIPK1	NM_001369807.1		c.26C>T	p.Ser9Leu	missense	Exon 2 of 16	NP_001356736.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIPK1	ENST00000426820.7	TSL:2 MANE Select	c.26C>T	p.Ser9Leu	missense	Exon 2 of 16	ENSP00000407442.3	Q86Z02-1
	HIPK1	ENST00000369558.5	TSL:1	c.26C>T	p.Ser9Leu	missense	Exon 2 of 16	ENSP00000358571.1	Q86Z02-1
	HIPK1	ENST00000369559.8	TSL:1	c.26C>T	p.Ser9Leu	missense	Exon 2 of 15	ENSP00000358572.4	Q86Z02-2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000324 AC: 8 AN: 247232 AF XY: 0.0000150

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000927 AC: 135 AN: 1456338 Hom.: 0 Cov.: 31 AF XY: 0.0000953 AC XY: 69 AN XY: 723950

African (AFR) AF: 0.0000300 AC: 1 AN: 33284

American (AMR) AF: 0.0000228 AC: 1 AN: 43904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25730

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 85832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1108884

Other (OTH) AF: 0.000133 AC: 8 AN: 60098

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74294

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.67
MVP		0.78
MPC		0.62
ClinPred		0.88	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.47
Mutation Taster		=64/36	polymorphism

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: rs371625292; hg19: chr1-114483031; COSMIC: COSV65786518;