chr14-77139317-A-G

Position:

• chr14-77139317-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174976.2(ZDHHC22):​c.422T>C​(p.Met141Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000069 in 1,449,066 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: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ZDHHC22 NM_174976.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19899678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC22	NM_174976.2	c.422T>C	p.Met141Thr	missense_variant	2/3	ENST00000319374.4
ZDHHC22	NM_001364172.1	c.422T>C	p.Met141Thr	missense_variant	2/3
ZDHHC22	XM_011536661.3	c.422T>C	p.Met141Thr	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC22	ENST00000319374.4	c.422T>C	p.Met141Thr	missense_variant	2/3	1	NM_174976.2	P1
TMEM63C	ENST00000557408.5	c.-237+22475A>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000690 AC: 10 AN: 1449066 Hom.: 0 Cov.: 31 AF XY: 0.00000556 AC XY: 4 AN XY: 719354

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome Cov.: 33

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 31, 2022

The c.422T>C (p.M141T) alteration is located in exon 2 (coding exon 1) of the ZDHHC22 gene. This alteration results from a T to C substitution at nucleotide position 422, causing the methionine (M) at amino acid position 141 to be replaced by a threonine (T). 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	0.19
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N
MutationTaster	Benign	0.94	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.087
Sift	Benign	0.18	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.47
MutPred		0.59		Loss of stability (P = 0.007);
MVP		0.13
MPC		0.52
ClinPred		0.12	T
GERP RS		1.8
Varity_R		0.063
gMVP		0.76

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: rs1887197983; hg19: chr14-77605660;