9-14619035-G-C

Position:

• chr9-14619035-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178566.6(ZDHHC21):​c.729C>G​(p.Ile243Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZDHHC21 NM_178566.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

Genes affected

ZDHHC21 (HGNC:20750): (zinc finger DHHC-type palmitoyltransferase 21) Enables palmitoyltransferase activity. Involved in peptidyl-L-cysteine S-palmitoylation. Located in Golgi apparatus and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZDHHC21	NM_178566.6	c.729C>G	p.Ile243Met	missense_variant	10/10	ENST00000380916.9	NP_848661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZDHHC21	ENST00000380916.9	c.729C>G	p.Ile243Met	missense_variant	10/10	1	NM_178566.6	ENSP00000370303	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460270 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726430

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Mar 07, 2024

The c.729C>G (p.I243M) alteration is located in exon 10 (coding exon 7) of the ZDHHC21 gene. This alteration results from a C to G substitution at nucleotide position 729, causing the isoleucine (I) at amino acid position 243 to be replaced by a methionine (M). 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	0.15
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0089	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.33
Sift	Benign	0.23	T
Sift4G	Benign	0.20	T
Polyphen		0.98	D
Vest4		0.66
MutPred		0.78		Gain of MoRF binding (P = 0.0783);
MVP		0.40
MPC		0.35
ClinPred		0.72	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.77

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: rs1824773225; hg19: chr9-14619033;