Genetic Variant ZDHHC5:p.Pro347Leu (chr11-57696791-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_015457.3(ZDHHC5):c.1040C>T(p.Pro347Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,614,014 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 (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ZDHHC5
NM_015457.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.07

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3079812).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC5	NM_015457.3 link	c.1040C>T	p.Pro347Leu	missense_variant	Exon 10 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.1040C>T	p.Pro347Leu	missense_variant	Exon 10 of 12	1	NM_015457.3	ENSP00000287169.3	Q9C0B5-1
ZDHHC5	ENST00000527985.5 link	c.881C>T	p.Pro294Leu	missense_variant	Exon 9 of 11	1		ENSP00000432202.1	Q9C0B5-2
ZDHHC5	ENST00000529480.1 link	n.1287C>T		non_coding_transcript_exon_variant	Exon 8 of 10	1
ZDHHC5	ENST00000529447.1 link	c.542C>T	p.Pro181Leu	missense_variant	Exon 6 of 7	5		ENSP00000435722.1	H0YEF4

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.0000159

AC:

AN:

251404

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461650

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000523

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:

0.0000564

Hom.:

Bravo

AF:

0.000144

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1040C>T (p.P347L) alteration is located in exon 10 (coding exon 9) of the ZDHHC5 gene. This alteration results from a C to T substitution at nucleotide position 1040, causing the proline (P) at amino acid position 347 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

0.32

BayesDel_addAF

Benign

0.0064

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

.;T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.4

.;M;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Uncertain

0.32

Sift

Benign

0.053

T;T;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.96

.;D;.

Vest4

0.81

MutPred

0.27

.;Loss of catalytic residue at P346 (P = 0.0116);.;

MVP

0.61

MPC

0.60

ClinPred

0.92

GERP RS

4.5

Varity_R

0.16

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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