Genetic Variant ZDHHC20:p.Arg246His (chr13-21387625-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_001330059.2(ZDHHC20):c.737G>A(p.Arg246His) variant causes a missense change. The variant allele was found at a frequency of 0.000077 in 1,453,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R246C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

ZDHHC20
NM_001330059.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83

Variant links:

Genes affected

ZDHHC20 (HGNC:20749): (zinc finger DHHC-type palmitoyltransferase 20) Enables protein-cysteine S-palmitoyltransferase activity and zinc ion binding activity. Involved in peptidyl-L-cysteine S-palmitoylation. Located in intracellular membrane-bounded organelle and plasma membrane. Is integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC20 links:

MIPEPP3 (HGNC:39458): (mitochondrial intermediate peptidase pseudogene 3)

MIPEPP3 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=0.03999874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC20	NM_001330059.2 link	c.737G>A	p.Arg246His	missense_variant	Exon 9 of 13	ENST00000400590.8	NP_001316988.1	Q5W0Z9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC20	ENST00000400590.8 link	c.737G>A	p.Arg246His	missense_variant	Exon 9 of 13	5	NM_001330059.2	ENSP00000383433.3		Q5W0Z9-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.0000960

AC:

AN:

114612

Hom.:

AF XY:

0.0000818

AC XY:

AN XY:

61088

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000288

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000507

Gnomad SAS exome

AF:

0.0000632

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000631

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000745

AC:

AN:

1302006

Hom.:

Cov.:

AF XY:

0.0000828

AC XY:

AN XY:

639792

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000194

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000223

Gnomad4 SAS exome

AF:

0.0000992

Gnomad4 FIN exome

AF:

0.0000438

Gnomad4 NFE exome

AF:

0.0000709

Gnomad4 OTH exome

AF:

0.0000562

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000278

AC:

ESP6500EA

AF:

0.000248

AC:

ExAC

AF:

0.0000398

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.737G>A (p.R246H) alteration is located in exon 9 (coding exon 9) of the ZDHHC20 gene. This alteration results from a G to A substitution at nucleotide position 737, causing the arginine (R) at amino acid position 246 to be replaced by a histidine (H). 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.057

.;T;T;.;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;.;D;D

M_CAP

Benign

0.063

MetaRNN

Benign

0.040

T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.4

M;.;M;M;M

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

D;D;D;D;D

REVEL

Benign

0.12

Sift

Uncertain

0.017

D;D;D;D;D

Sift4G

Benign

0.069

T;T;T;T;T

Polyphen

0.64

P;B;.;.;.

Vest4

0.38

MVP

0.32

MPC

1.6

ClinPred

0.23

GERP RS

5.4

Varity_R

0.59

gMVP

0.81

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