13-21376655-C-A

Variant names:

• chr13-21376655-C-A
• rs1276415331
• NM_001330059.2:c.*41G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153251.4(ZDHHC20):​c.1058G>T​(p.Gly353Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000159 in 1,257,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G353D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: ZDHHC20 NM_153251.4 missense, splice_region
• Scores: Splicing: ADA: 0.7899
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.35
• Publications: 0 publications found

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]

ENSG00000291046 (HGNC:):

MIPEPP3 (HGNC:39458): (mitochondrial intermediate peptidase pseudogene 3)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3268341).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153251.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC20	NM_001330059.2	MANE Select	c.*41G>T		splice_region	Exon 13 of 13	NP_001316988.1	Q5W0Z9-1
	ZDHHC20	NM_001330059.2	MANE Select	c.*41G>T		3_prime_UTR	Exon 13 of 13	NP_001316988.1	Q5W0Z9-1
	ZDHHC20	NM_153251.4		c.1058G>T	p.Gly353Val	missense splice_region	Exon 12 of 12	NP_694983.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC20	ENST00000400590.8	TSL:5 MANE Select	c.*41G>T		splice_region	Exon 13 of 13	ENSP00000383433.3	Q5W0Z9-1
	ZDHHC20	ENST00000382466.7	TSL:1	c.1058G>T	p.Gly353Val	missense splice_region	Exon 12 of 12	ENSP00000371905.3	Q5W0Z9-3
	ZDHHC20	ENST00000320220.13	TSL:1	c.*143G>T		splice_region	Exon 13 of 13	ENSP00000313583.9	Q5W0Z9-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000159 AC: 2 AN: 1257648 Hom.: 0 Cov.: 20 AF XY: 0.00000322 AC XY: 2 AN XY: 621560

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26766

American (AMR) AF: 0.00 AC: 0 AN: 22284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21762

East Asian (EAS) AF: 0.00 AC: 0 AN: 32898

South Asian (SAS) AF: 0.00 AC: 0 AN: 67854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5200

European-Non Finnish (NFE) AF: 0.00000204 AC: 2 AN: 981526

Other (OTH) AF: 0.00 AC: 0 AN: 52172

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.0012
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.99	T
PhyloP100		4.3
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.0090	B
Vest4		0.64
MutPred		0.29		Gain of sheet (P = 0.0266)
MVP		0.40
MPC		1.4
ClinPred		0.87	D
GERP RS		5.3
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.62		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1276415331; hg19: chr13-21950794;