chr19-40380773-A-C

Position:

• chr19-40380773-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: HIPK4 NM_144685.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.36

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]

ACMG classification

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/exons	MANE	Protein	UniProt
HIPK4	NM_144685.5	c.1218T>G	p.Ser406Arg	missense_variant	3/4	ENST00000291823.3	NP_653286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIPK4	ENST00000291823.3	c.1218T>G	p.Ser406Arg	missense_variant	3/4	1	NM_144685.5	ENSP00000291823.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152238 Hom.: 2 Cov.: 32

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.: 35 AF XY: 0.00513 AC XY: 696 AN XY: 135774

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.: 43 Cov.: 33 AF XY: 0.00127 AC XY: 927 AN XY: 727210

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.: 2 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74490

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.: 1

Bravo AF: 0.00386

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00533 AC: 647

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.0030
DANN	Benign	0.92
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.072
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.022	D
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.10		Loss of glycosylation at S406 (P = 0.016);
MVP		0.50
MPC		0.36
ClinPred		0.0044	T
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

Other links and lift over

dbSNP: rs56094851; hg19: chr19-40886680;