chr13-21413729-A-G

Position:

• chr13-21413729-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001330059.2(ZDHHC20):​c.293T>C​(p.Phe98Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZDHHC20 NM_001330059.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

Genes affected

ZDHHC20 (HGNC:20749): (zinc finger DHHC-type palmitoyltransferase 20) Enables protein-cysteine S-palmitoyltransferase activity and zinc ion binding activity. Involved in peptidyl-L-cysteine S-palmitoylation. Located in intracellular membrane-bounded organelle and plasma membrane. Is integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.03418809).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC20	NM_001330059.2	c.293T>C	p.Phe98Ser	missense_variant	4/13	ENST00000400590.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC20	ENST00000400590.8	c.293T>C	p.Phe98Ser	missense_variant	4/13	5	NM_001330059.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459524 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000302

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

Sep 12, 2023

The c.293T>C (p.F98S) alteration is located in exon 4 (coding exon 4) of the ZDHHC20 gene. This alteration results from a T to C substitution at nucleotide position 293, causing the phenylalanine (F) at amino acid position 98 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	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0022	.;T;T;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.68	T;T;.;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.034	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N;.;N;N;N
MutationTaster	Benign	0.85	N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	2.4	N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.0010	B;B;.;.;.
Vest4		0.19
MutPred		0.28		.;Gain of phosphorylation at F35 (P = 0.0167);.;.;.;
MVP		0.030
MPC		1.1
ClinPred		0.53	D
GERP RS		1.3
Varity_R		0.13
gMVP		0.60

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

Other links and lift over

dbSNP: rs1016252535; hg19: chr13-21987868;