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

Variant summary

Our verdict is Likely benign. The variant received -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. 14/22 in silico tools predict a benign outcome for this variant. 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. R449P) 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

Publications

0 publications found

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:

ENSG00000299506 (HGNC:):

ENSG00000299506 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323627.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC1	NM_001323627.2	MANE Select	c.1346G>A	p.Arg449Gln	missense	Exon 12 of 12	NP_001310556.1	I3L202
	ZDHHC1	NM_013304.3		c.1411G>A	p.Asp471Asn	missense	Exon 11 of 11	NP_037436.1	Q8WTX9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZDHHC1	ENST00000565726.3	TSL:5 MANE Select	c.1346G>A	p.Arg449Gln	missense	Exon 12 of 12	ENSP00000459264.2	I3L202
ZDHHC1	ENST00000348579.6	TSL:1	c.1411G>A	p.Asp471Asn	missense	Exon 11 of 11	ENSP00000340299.2	Q8WTX9
ZDHHC1	ENST00000902881.1		c.1346G>A	p.Arg449Gln	missense	Exon 12 of 12	ENSP00000572940.1

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

African (AFR)

AF:

0.00

AC:

AN:

23572

American (AMR)

AF:

0.00

AC:

AN:

10704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16882

East Asian (EAS)

AF:

0.00

AC:

AN:

26982

South Asian (SAS)

AF:

0.00

AC:

AN:

47732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3284

European-Non Finnish (NFE)

AF:

0.0000529

AC:

AN:

983494

Other (OTH)

AF:

0.0000209

AC:

AN:

47944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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

AF:

0.0000595

AC:

AN:

151374

Hom.:

Cov.:

AF XY:

0.0000946

AC XY:

AN XY:

73958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41080

American (AMR)

AF:

0.00

AC:

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67894

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000648

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.1

(source)

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

PhyloP100

-0.66

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

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over