chr13-21376655-C-T

Variant names:

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

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>A​(p.Gly353Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000376 in 1,409,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: ZDHHC20 NM_153251.4 missense, splice_region
• Scores: Splicing: ADA: 0.7359
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.30644625).

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>A		splice_region	Exon 13 of 13	NP_001316988.1	Q5W0Z9-1
	ZDHHC20	NM_001330059.2	MANE Select	c.*41G>A		3_prime_UTR	Exon 13 of 13	NP_001316988.1	Q5W0Z9-1
	ZDHHC20	NM_153251.4		c.1058G>A	p.Gly353Asp	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>A		splice_region	Exon 13 of 13	ENSP00000383433.3	Q5W0Z9-1
	ZDHHC20	ENST00000382466.7	TSL:1	c.1058G>A	p.Gly353Asp	missense splice_region	Exon 12 of 12	ENSP00000371905.3	Q5W0Z9-3
	ZDHHC20	ENST00000320220.13	TSL:1	c.*143G>A		splice_region	Exon 13 of 13	ENSP00000313583.9	Q5W0Z9-4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152034 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000183 AC: 2 AN: 109350 AF XY: 0.0000342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000432

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 49 AN: 1257642 Hom.: 0 Cov.: 20 AF XY: 0.0000322 AC XY: 20 AN XY: 621554

⚠️ 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: 0.0000458 AC: 45 AN: 981520

Other (OTH) AF: 0.0000767 AC: 4 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 AF: 0.0000263 AC: 4 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41504

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000387 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.045	D
Polyphen		0.025	B
Vest4		0.61
MVP		0.52
MPC		1.7
ClinPred		0.91	D
GERP RS		5.3
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.74
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1276415331; hg19: chr13-21950794;