19-40383787-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_144685.5(HIPK4):c.818C>T(p.Thr273Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000743 in 1,601,704 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000074 ( 1 hom. )
Consequence
HIPK4
NM_144685.5 missense
NM_144685.5 missense
Scores
4
6
9
Clinical Significance
Conservation
PhyloP100: 4.21
Genes affected
HIPK4 (HGNC:19007): (homeodomain interacting protein kinase 4) This gene encodes a member of the homeodomain interacting protein kinase (HIPK) family of proteins. While other members of this family are found throughout vertebrates, this member is present only in mammals. Compared to other members of this family, the encoded protein lacks a nuclear localization signal and a C-terminal autoinhibitory domain. The encoded protein exhibits kinase activity and may phosphorylate the tumor suppressor protein p53. [provided by RefSeq, Jul 2016]
PLD3 (HGNC:17158): (phospholipase D family member 3) This gene encodes a member of the phospholipase D (PLD) family of enzymes that catalyze the hydrolysis of membrane phospholipids. The encoded protein is a single-pass type II membrane protein and contains two PLD phosphodiesterase domains. This protein influences processing of amyloid-beta precursor protein. Mutations in this gene are associated with Alzheimer disease risk. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.30320832).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HIPK4 | NM_144685.5 | c.818C>T | p.Thr273Met | missense_variant | 2/4 | ENST00000291823.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HIPK4 | ENST00000291823.3 | c.818C>T | p.Thr273Met | missense_variant | 2/4 | 1 | NM_144685.5 | P1 | |
PLD3 | ENST00000700620.1 | c.*51-3525G>A | intron_variant | P1 | |||||
PLD3 | ENST00000700633.1 | c.*51-3712G>A | intron_variant | P1 | |||||
PLD3 | ENST00000700634.1 | c.*50+5564G>A | intron_variant | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152002Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000110 AC: 27AN: 246278Hom.: 0 AF XY: 0.0000973 AC XY: 13AN XY: 133658
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GnomAD4 exome AF: 0.0000738 AC: 107AN: 1449584Hom.: 1 Cov.: 31 AF XY: 0.0000779 AC XY: 56AN XY: 719056
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GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74378
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2023 | The c.818C>T (p.T273M) alteration is located in exon 2 (coding exon 2) of the HIPK4 gene. This alteration results from a C to T substitution at nucleotide position 818, causing the threonine (T) at amino acid position 273 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at