rs1887197983

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 14/22 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.23

Publications

0 publications found

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:

ENSG00000259164 (HGNC:):

ENSG00000259164 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 Gene-Disease associations (from GenCC):

spastic paraplegia 87, autosomal recessive
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics

TMEM63C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
ZDHHC22	NM_174976.2 link	c.422T>C	p.Met141Thr	missense_variant	Exon 2 of 3	ENST00000319374.4	NP_777636.2	Q8N966
ZDHHC22	NM_001364172.1 link	c.422T>C	p.Met141Thr	missense_variant	Exon 2 of 3		NP_001351101.1
ZDHHC22	XM_011536661.3 link	c.422T>C	p.Met141Thr	missense_variant	Exon 2 of 3		XP_011534963.1	Q8N966

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZDHHC22	ENST00000319374.4 link	c.422T>C	p.Met141Thr	missense_variant	Exon 2 of 3	1	NM_174976.2	ENSP00000318222.4	Q8N966
ENSG00000259164	ENST00000557752.1 link	n.136+33473A>G		intron_variant	Intron 2 of 5	5		ENSP00000456507.1	H3BS24
TMEM63C	ENST00000557408.5 link	c.-237+22475A>G		intron_variant	Intron 1 of 3	4		ENSP00000450879.1	G3V2V1
ZDHHC22	ENST00000555389.1 link	c.*93T>C		downstream_gene_variant		4		ENSP00000451337.1	G3V3N3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000690

AC:

AN:

1449066

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

42524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25886

East Asian (EAS)

AF:

0.0000511

AC:

AN:

39152

South Asian (SAS)

AF:

0.00

AC:

AN:

83776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52492

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106182

Other (OTH)

AF:

0.000100

AC:

AN:

60008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

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

Mar 31, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.056

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.61

M_CAP

Benign

0.0045

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

PhyloP100

4.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.2

REVEL

Benign

0.087

Sift

Benign

0.18

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.47

MutPred

0.59

Loss of stability (P = 0.007);

MVP

0.13

MPC

0.52

ClinPred

0.12

GERP RS

1.8

Varity_R

0.063

gMVP

0.76

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over