1-113940496-G-T

Position:

• chr1-113940496-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_198268.3(HIPK1):​c.113G>T​(p.Ser38Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HIPK1 NM_198268.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22186208).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIPK1	NM_198268.3	c.113G>T	p.Ser38Ile	missense_variant	2/16	ENST00000426820.7	NP_938009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIPK1	ENST00000426820.7	c.113G>T	p.Ser38Ile	missense_variant	2/16	2	NM_198268.3	ENSP00000407442.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.113G>T (p.S38I) alteration is located in exon 2 (coding exon 1) of the HIPK1 gene. This alteration results from a G to T substitution at nucleotide position 113, causing the serine (S) at amino acid position 38 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;T;T;.;T;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;.;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.;L;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	.;N;.;N;N;N;D;D
REVEL	Benign	0.083
Sift	Uncertain	0.0070	.;D;.;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T;D;D
Polyphen		0.61	P;P;.;P;.;.;.;.
Vest4		0.43
MutPred		0.26		Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);
MVP		0.58
MPC		0.92
ClinPred		0.81	D
GERP RS		4.0
Varity_R		0.17
gMVP		0.46

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: rs1670575600; hg19: chr1-114483118; COSMIC: COSV65786686;