1-26850334-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032283.3(ZDHHC18):c.680A>G(p.Asn227Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZDHHC18 NM_032283.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.94

Genes affected

ZDHHC18 (HGNC:20712): (zinc finger DHHC-type palmitoyltransferase 18) Enables palmitoyltransferase activity. Involved in peptidyl-L-cysteine S-palmitoylation. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC18	NM_032283.3	c.680A>G	p.Asn227Ser	missense_variant	4/8	ENST00000374142.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC18	ENST00000374142.9	c.680A>G	p.Asn227Ser	missense_variant	4/8	1	NM_032283.3	P1
ZDHHC18	ENST00000374141.6	c.275A>G	p.Asn92Ser	missense_variant	4/8	2
ZDHHC18	ENST00000534643.5	c.275A>G	p.Asn92Ser	missense_variant	4/6	4
ZDHHC18	ENST00000488397.3			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.680A>G (p.N227S) alteration is located in exon 4 (coding exon 4) of the ZDHHC18 gene. This alteration results from a A to G substitution at nucleotide position 680, causing the asparagine (N) at amino acid position 227 to be replaced by a serine (S). 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	0.85
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.4	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0080	D;D;T
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.77		Gain of glycosylation at N227 (P = 0.0197);.;.;
MVP		0.45
MPC		1.4
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-27176825;