19-40380773-A-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_144685.5(HIPK4):c.1218T>G(p.Ser406Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,180 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 43 hom. )

Consequence

HIPK4
NM_144685.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.36

Variant links:

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]

HIPK4 links:

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]

PLD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032717586).

BP6

Variant 19-40380773-A-C is Benign according to our data. Variant chr19-40380773-A-C is described in ClinVar as [Benign]. Clinvar id is 778597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00148 (2161/1461824) while in subpopulation AMR AF= 0.0376 (1680/44724). AF 95% confidence interval is 0.0361. There are 43 homozygotes in gnomad4_exome. There are 927 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIPK4	NM_144685.5 link	c.1218T>G	p.Ser406Arg	missense_variant	Exon 3 of 4	ENST00000291823.3	NP_653286.2	Q8NE63A0A140VJL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIPK4	ENST00000291823.3 link	c.1218T>G	p.Ser406Arg	missense_variant	Exon 3 of 4	1	NM_144685.5	ENSP00000291823.1		Q8NE63

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

300

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00596

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00653

AC:

1639

AN:

251024

Hom.:

AF XY:

0.00513

AC XY:

696

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.0414

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00709

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00148

AC:

2161

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

927

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0376

Gnomad4 ASJ exome

AF:

0.00298

Gnomad4 EAS exome

AF:

0.00496

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000701

Gnomad4 OTH exome

AF:

0.00154

GnomAD4 genome

AF:

0.00198

AC:

302

AN:

152356

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.0150

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00598

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000450

Hom.:

Bravo

AF:

0.00386

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00533

AC:

647

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.0030

DANN

Benign

0.92

DEOGEN2

Benign

0.018

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.6

REVEL

Benign

0.072

Sift

Uncertain

0.023

Sift4G

Uncertain

0.022

Polyphen

0.0010

Vest4

0.18

MutPred

0.10

Loss of glycosylation at S406 (P = 0.016);

MVP

0.50

MPC

0.36

ClinPred

0.0044

GERP RS

-8.4

Varity_R

0.082

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over