Genetic Variant ZDHHC1:p.Arg449Gln (chr16-67394713-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001323627.2(ZDHHC1):c.1346G>A(p.Arg449Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000463 in 1,339,746 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 (★). Synonymous variant affecting the same amino acid position (i.e. R449R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

ZDHHC1
NM_001323627.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.663

Variant links:

Genes affected

ZDHHC1 (HGNC:17916): (zinc finger DHHC-type containing 1) Enables palmitoyltransferase activity. Involved in antiviral innate immune response; positive regulation of defense response to virus by host; and protein palmitoylation. Located in Golgi apparatus and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZDHHC1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049999923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC1	NM_001323627.2 link	c.1346G>A	p.Arg449Gln	missense_variant	Exon 12 of 12	ENST00000565726.3	NP_001310556.1	Q8WTX9I3L202

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZDHHC1	ENST00000565726.3 link	c.1346G>A	p.Arg449Gln	missense_variant	Exon 12 of 12	5	NM_001323627.2	ENSP00000459264.2	I3L202
ZDHHC1	ENST00000348579.6 link	c.1411G>A	p.Asp471Asn	missense_variant	Exon 11 of 11	1		ENSP00000340299.2	Q8WTX9
ZDHHC1	ENST00000566075.1 link	n.901G>A		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0000595

AC:

AN:

151374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1188372

Hom.:

Cov.:

AF XY:

0.0000483

AC XY:

AN XY:

579248

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:

0.0000529

Gnomad4 OTH exome

AF:

0.0000209

GnomAD4 genome

AF:

0.0000595

AC:

AN:

151374

Hom.:

Cov.:

AF XY:

0.0000946

AC XY:

AN XY:

73958

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000648

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1411G>A (p.D471N) alteration is located in exon 11 (coding exon 10) of the ZDHHC1 gene. This alteration results from a G to A substitution at nucleotide position 1411, causing the aspartic acid (D) at amino acid position 471 to be replaced by an asparagine (N). 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

0.14

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.1

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0082

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.38

M_CAP

Benign

0.038

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.17

REVEL

Benign

0.062

Sift

Uncertain

0.018

Sift4G

Benign

0.075

Polyphen

0.0010

Vest4

0.049

MutPred

0.11

Gain of catalytic residue at D471 (P = 0.033);

MVP

0.030

MPC

1.4

ClinPred

0.35

GERP RS

-0.42

Varity_R

0.034

gMVP

0.063

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