chr1-113957258-G-A

Variant names:

• chr1-113957258-G-A
• rs776873633
• NM_198268.3:c.1727G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198268.3(HIPK1):​c.1727G>A​(p.Ser576Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: HIPK1 NM_198268.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05521959).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIPK1	NM_198268.3	c.1727G>A	p.Ser576Asn	missense_variant	Exon 7 of 16	ENST00000426820.7	NP_938009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIPK1	ENST00000426820.7	c.1727G>A	p.Ser576Asn	missense_variant	Exon 7 of 16	2	NM_198268.3	ENSP00000407442.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 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: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251178 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461588 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1727G>A (p.S576N) alteration is located in exon 7 (coding exon 6) of the HIPK1 gene. This alteration results from a G to A substitution at nucleotide position 1727, causing the serine (S) at amino acid position 576 to be replaced by an asparagine (N). 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	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Benign	0.31
DEOGEN2	Benign	0.050	T;.;T;T;T;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	.;T;T;T;.;T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.055	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.15	N;N;.;N;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.1	.;N;.;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	.;T;.;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.;B
Vest4		0.10
MutPred		0.13		Loss of glycosylation at S576 (P = 0.1166);Loss of glycosylation at S576 (P = 0.1166);Loss of glycosylation at S576 (P = 0.1166);Loss of glycosylation at S576 (P = 0.1166);Loss of glycosylation at S576 (P = 0.1166);.;.;
MVP		0.39
MPC		0.20
ClinPred		0.21	T
GERP RS		4.2
Varity_R		0.043
gMVP		0.39

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: rs776873633; hg19: chr1-114499880;