Genetic Variant ZDHHC1:p.Arg306Gln (chr16-67398222-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001323627.2(ZDHHC1):c.917G>A(p.Arg306Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,138 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ZDHHC1
NM_001323627.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.127

Variant links:

Genes affected

ZDHHC1 (HGNC:17916): (zinc finger DHHC-type containing 1) Enables palmitoyltransferase activity. Involved in antiviral innate immune response; positive regulation of defense response to virus by host; and protein palmitoylation. Located in Golgi apparatus and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01990652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC1	NM_001323627.2 link	c.917G>A	p.Arg306Gln	missense_variant	Exon 8 of 12	ENST00000565726.3	NP_001310556.1	Q8WTX9I3L202

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZDHHC1	ENST00000565726.3 link	c.917G>A	p.Arg306Gln	missense_variant	Exon 8 of 12	5	NM_001323627.2	ENSP00000459264.2	I3L202
ZDHHC1	ENST00000348579.6 link	c.917G>A	p.Arg306Gln	missense_variant	Exon 8 of 11	1		ENSP00000340299.2	Q8WTX9
ZDHHC1	ENST00000562122.1 link	n.535G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251264

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000198

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000125

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000427

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.917G>A (p.R306Q) alteration is located in exon 8 (coding exon 7) of the ZDHHC1 gene. This alteration results from a G to A substitution at nucleotide position 917, causing the arginine (R) at amino acid position 306 to be replaced by a glutamine (Q). 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

0.083

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

.;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

.;N

REVEL

Benign

0.069

Sift

Benign

0.056

.;T

Sift4G

Benign

0.60

.;T

Polyphen

0.052

.;B

Vest4

0.25

MVP

0.048

MPC

0.19

ClinPred

0.11

GERP RS

-1.2

Varity_R

0.11

gMVP

0.30

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