Variant 14-77139590-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_174976.2(ZDHHC22):c.149A>G(p.His50Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,442,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H50Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZDHHC22
NM_174976.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.81

Variant links:

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]

ZDHHC22 links:

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]

TMEM63C links:

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ACMG classification

Classification made for transcript

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
ZDHHC22	NM_174976.2 linkuse as main transcript	c.149A>G	p.His50Arg	missense_variant	2/3	ENST00000319374.4
ZDHHC22	NM_001364172.1 linkuse as main transcript	c.149A>G	p.His50Arg	missense_variant	2/3
ZDHHC22	XM_011536661.3 linkuse as main transcript	c.149A>G	p.His50Arg	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ZDHHC22	ENST00000319374.4 linkuse as main transcript	c.149A>G	p.His50Arg	missense_variant	2/3	1	NM_174976.2	P1
ZDHHC22	ENST00000555389.1 linkuse as main transcript	c.149A>G	p.His50Arg	missense_variant	2/2	4
TMEM63C	ENST00000557408.5 linkuse as main transcript	c.-237+22748T>C		intron_variant		4
ZDHHC22	ENST00000555327.1 linkuse as main transcript			downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1442590

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715486

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.149A>G (p.H50R) 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 149, causing the histidine (H) at amino acid position 50 to be replaced by an arginine (R). 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

0.70

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

0.097

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0060

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.38

B;.

Vest4

0.84

MutPred

0.69

Loss of catalytic residue at G51 (P = 0.0868);Loss of catalytic residue at G51 (P = 0.0868);

MVP

0.21

MPC

1.4

ClinPred

0.98

GERP RS

5.5

Varity_R

0.63

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over