chr3-113954212-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001320466.2(ZDHHC23):​c.674C>T​(p.Pro225Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

ZDHHC23
NM_001320466.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20
Variant links:
Genes affected
ZDHHC23 (HGNC:28654): (zinc finger DHHC-type palmitoyltransferase 23) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Involved in protein localization to plasma membrane and protein palmitoylation. Predicted to be located in Golgi membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

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=0.03956291).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ZDHHC23NM_001320466.2 linkuse as main transcriptc.674C>T p.Pro225Leu missense_variant 3/5 ENST00000638807.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ZDHHC23ENST00000638807.2 linkuse as main transcriptc.674C>T p.Pro225Leu missense_variant 3/55 NM_001320466.2 P1
ZDHHC23ENST00000330212.7 linkuse as main transcriptc.674C>T p.Pro225Leu missense_variant 3/61
ZDHHC23ENST00000498275.5 linkuse as main transcriptc.656C>T p.Pro219Leu missense_variant 4/72
ZDHHC23ENST00000478793.1 linkuse as main transcriptc.674C>T p.Pro225Leu missense_variant, NMD_transcript_variant 3/72

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152170
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000637
AC:
16
AN:
251286
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
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:
0.000106
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000153
AC:
224
AN:
1461876
Hom.:
0
Cov.:
30
AF XY:
0.000144
AC XY:
105
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000192
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.000147
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 27, 2023The c.674C>T (p.P225L) alteration is located in exon 3 (coding exon 2) of the ZDHHC23 gene. This alteration results from a C to T substitution at nucleotide position 674, causing the proline (P) at amino acid position 225 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
0.070
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
14
DANN
Benign
0.25
DEOGEN2
Benign
0.031
T;T;.
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.77
T;T;T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.040
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.1
L;.;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.80
N;N;.
REVEL
Benign
0.032
Sift
Benign
0.67
T;T;.
Sift4G
Benign
0.67
T;T;.
Polyphen
0.0
B;.;.
Vest4
0.082
MVP
0.030
MPC
0.20
ClinPred
0.023
T
GERP RS
2.8
Varity_R
0.043

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.

Other links and lift over

dbSNP: rs147787442; hg19: chr3-113673059; API