Genetic Variant ZDHHC5:p.Ser274Leu (chr11-57693851-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015457.3(ZDHHC5):c.821C>T(p.Ser274Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000802 in 1,611,952 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 1 hom. )

Consequence

ZDHHC5
NM_015457.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.71

Variant links:

Genes affected

ZDHHC5 (HGNC:18472): (zinc finger DHHC-type palmitoyltransferase 5) Enables palmitoyltransferase activity. Involved in positive regulation of pattern recognition receptor signaling pathway and positive regulation of protein localization to plasma membrane. Acts upstream of or within protein palmitoylation. Located in phagocytic vesicle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0206815).

BS2

High AC in GnomAd4 at 105 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC5	NM_015457.3 link	c.821C>T	p.Ser274Leu	missense_variant	Exon 8 of 12	ENST00000287169.8	NP_056272.2	Q9C0B5-1A0A024R546

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZDHHC5	ENST00000287169.8 link	c.821C>T	p.Ser274Leu	missense_variant	Exon 8 of 12	1	NM_015457.3	ENSP00000287169.3	Q9C0B5-1
ZDHHC5	ENST00000527985.5 link	c.662C>T	p.Ser221Leu	missense_variant	Exon 7 of 11	1		ENSP00000432202.1	Q9C0B5-2
ZDHHC5	ENST00000529480.1 link	n.1068C>T		non_coding_transcript_exon_variant	Exon 6 of 10	1
ZDHHC5	ENST00000529447.1 link	c.323C>T	p.Ser108Leu	missense_variant	Exon 4 of 7	5		ENSP00000435722.1	H0YEF4

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000867

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000784

AC:

194

AN:

247568

Hom.:

AF XY:

0.000979

AC XY:

131

AN XY:

133750

show subpopulations

Gnomad AFR exome

AF:

0.000379

Gnomad AMR exome

AF:

0.000817

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000401

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000813

AC:

1187

AN:

1459688

Hom.:

Cov.:

AF XY:

0.000876

AC XY:

636

AN XY:

725910

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000362

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000816

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.000690

AC:

105

AN:

152264

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000867

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000975

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000815

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.821C>T (p.S274L) alteration is located in exon 8 (coding exon 7) of the ZDHHC5 gene. This alteration results from a C to T substitution at nucleotide position 821, causing the serine (S) at amino acid position 274 to be replaced by a leucine (L). 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

0.19

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;T;T

Eigen

Benign

-0.027

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.3

.;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.3

N;D;N

REVEL

Benign

0.26

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.71

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.24

MVP

0.82

MPC

0.17

ClinPred

0.047

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.46

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