14-77139549-T-C

Variant summary

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

The NM_174976.2(ZDHHC22):c.190A>G(p.Asn64Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZDHHC22 NM_174976.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62

Genes affected

ZDHHC22 (HGNC:20106): (zinc finger DHHC-type palmitoyltransferase 22) Predicted to enable protein-cysteine S-palmitoyltransferase activity. Involved in protein localization to plasma membrane and protein palmitoylation. Located in Golgi apparatus; endoplasmic reticulum; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM63C (HGNC:23787): (transmembrane protein 63C) Enables calcium activated cation channel activity. Involved in cation transport. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. Biomarker of focal segmental glomerulosclerosis. [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	UniProt
ZDHHC22	NM_174976.2	c.190A>G	p.Asn64Asp	missense_variant	2/3	ENST00000319374.4
ZDHHC22	NM_001364172.1	c.190A>G	p.Asn64Asp	missense_variant	2/3
ZDHHC22	XM_011536661.3	c.190A>G	p.Asn64Asp	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC22	ENST00000319374.4	c.190A>G	p.Asn64Asp	missense_variant	2/3	1	NM_174976.2	P1
ZDHHC22	ENST00000555389.1	c.190A>G	p.Asn64Asp	missense_variant	2/2	4
TMEM63C	ENST00000557408.5	c.-237+22707T>C		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454412 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

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.: 33

ExAC AF: 0.00000828 AC: 1

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

Oct 02, 2023

The c.190A>G (p.N64D) alteration is located in exon 2 (coding exon 1) of the ZDHHC22 gene. This alteration results from a A to G substitution at nucleotide position 190, causing the asparagine (N) at amino acid position 64 to be replaced by an aspartic acid (D). 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	0.94
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.45		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.54
MPC		1.4
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.98

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: rs775087356; hg19: chr14-77605892;