chr1-113940923-T-G

Variant names:

• chr1-113940923-T-G
• rs1670606425
• NM_198268.3:c.540T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_198268.3(HIPK1):​c.540T>G​(p.His180Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H180R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HIPK1 NM_198268.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.540T>G	p.His180Gln	missense	Exon 2 of 16	NP_938009.1	Q86Z02-1
	HIPK1	NM_001369806.1		c.540T>G	p.His180Gln	missense	Exon 2 of 16	NP_001356735.1	Q86Z02-1
	HIPK1	NM_001369807.1		c.540T>G	p.His180Gln	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.540T>G	p.His180Gln	missense	Exon 2 of 16	ENSP00000407442.3	Q86Z02-1
	HIPK1	ENST00000369558.5	TSL:1	c.540T>G	p.His180Gln	missense	Exon 2 of 16	ENSP00000358571.1	Q86Z02-1
	HIPK1	ENST00000369559.8	TSL:1	c.540T>G	p.His180Gln	missense	Exon 2 of 15	ENSP00000358572.4	Q86Z02-2

Frequencies

GnomAD3 genomes AF: 0.0000725 AC: 11 AN: 151668 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000571

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000627 AC: 896 AN: 1429438 Hom.: 0 Cov.: 32 AF XY: 0.000567 AC XY: 404 AN XY: 712114

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000488 AC: 16 AN: 32766

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.000193 AC: 5 AN: 25852

East Asian (EAS) AF: 0.000178 AC: 7 AN: 39338

South Asian (SAS) AF: 0.000257 AC: 22 AN: 85570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5694

European-Non Finnish (NFE) AF: 0.000753 AC: 816 AN: 1083278

Other (OTH) AF: 0.000489 AC: 29 AN: 59254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000725 AC: 11 AN: 151788 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74220

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.000571 AC: 6 AN: 10500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67858

Other (OTH) AF: 0.00 AC: 0 AN: 2108

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.56		Gain of loop (P = 0.1069)
MVP		0.70
MPC		1.7
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.63
Mutation Taster		=74/26	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: rs1670606425; hg19: chr1-114483545;