Genetic Variant ZDHHC5:p.Thr350Ile (chr11-57696800-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_015457.3(ZDHHC5):c.1049C>T(p.Thr350Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,613,964 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 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a modified_residue Phosphothreonine (size 0) in uniprot entity ZDHC5_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.3695389).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC5	NM_015457.3 link	c.1049C>T	p.Thr350Ile	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.1049C>T	p.Thr350Ile	missense_variant	Exon 10 of 12	1	NM_015457.3	ENSP00000287169.3	Q9C0B5-1
ZDHHC5	ENST00000527985.5 link	c.890C>T	p.Thr297Ile	missense_variant	Exon 9 of 11	1		ENSP00000432202.1	Q9C0B5-2
ZDHHC5	ENST00000529480.1 link	n.1296C>T		non_coding_transcript_exon_variant	Exon 8 of 10	1
ZDHHC5	ENST00000529447.1 link	c.551C>T	p.Thr184Ile	missense_variant	Exon 6 of 7	5		ENSP00000435722.1	H0YEF4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000479

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251428

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

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:

0.000479

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1049C>T (p.T350I) 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 1049, causing the threonine (T) at amino acid position 350 to be replaced by an isoleucine (I). 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

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.044

.;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.79

T;T;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.7

.;L;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.98

.;D;.

Vest4

0.66

MutPred

0.17

.;Loss of glycosylation at T350 (P = 0.0092);.;

MVP

0.38

MPC

0.27

ClinPred

0.63

GERP RS

5.5

Varity_R

0.12

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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