dbSNP rs759167348: ZDHHC4:p.Leu112Val (chr7-6582215-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001134389.2(ZDHHC4):c.334C>G(p.Leu112Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ZDHHC4
NM_001134389.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0590

Variant links:

Genes affected

ZDHHC4 (HGNC:18471): (zinc finger DHHC-type palmitoyltransferase 4) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Predicted to be involved in peptidyl-L-cysteine S-palmitoylation and protein targeting to membrane. Located in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC4 links:

ENSG00000232581 (HGNC:):

ENSG00000232581 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34612054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC4	NM_001134389.2 link	c.334C>G	p.Leu112Val	missense_variant	Exon 5 of 8	ENST00000335965.11	NP_001127861.1	Q9NPG8A0A024QZS8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC4	ENST00000335965.11 link	c.334C>G	p.Leu112Val	missense_variant	Exon 5 of 8	1	NM_001134389.2	ENSP00000337475.6		Q9NPG8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251434

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111962

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.334C>G (p.L112V) alteration is located in exon 5 (coding exon 3) of the ZDHHC4 gene. This alteration results from a C to G substitution at nucleotide position 334, causing the leucine (L) at amino acid position 112 to be replaced by a valine (V). 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

0.086

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0030

T;T;T;T;T;.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.59

.;.;T;.;.;T;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.35

T;T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.5

M;M;M;M;M;.;M

PhyloP100

-0.059

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.69

N;N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.31

T;T;T;T;T;T;T

Sift4G

Benign

0.42

T;T;T;T;T;T;T

Polyphen

0.89

P;P;P;P;P;D;P

Vest4

0.14

MutPred

0.67

Gain of catalytic residue at L112 (P = 0.103);Gain of catalytic residue at L112 (P = 0.103);Gain of catalytic residue at L112 (P = 0.103);Gain of catalytic residue at L112 (P = 0.103);Gain of catalytic residue at L112 (P = 0.103);Gain of catalytic residue at L112 (P = 0.103);Gain of catalytic residue at L112 (P = 0.103);

MVP

0.42

MPC

0.11

ClinPred

0.17

GERP RS

-0.043

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.028

gMVP

0.51

Mutation Taster

=92/8

polymorphism

(source)

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 for variant 7:6582215 C>G . It may be empty.

rs759167348

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over