Genetic Variant ZCCHC13:p.Arg88His (chrX-74304529-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_203303.3(ZCCHC13):c.263G>A(p.Arg88His) variant causes a missense change. The variant allele was found at a frequency of 0.000135 in 1,210,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 0 hom. 43 hem. )

Consequence

ZCCHC13
NM_203303.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.38

Publications

3 publications found

Variant links:

Genes affected

ZCCHC13 (HGNC:31749): (zinc finger CCHC-type containing 13) This gene appears to represent an intronless retrocopy of a related multi-exon gene located on chromosome 3. However, the CDS of this intronless gene remains relatively intact, it is conserved in other mammalian species, it is known to be transcribed, and it is therefore thought to encode a functional protein. The encoded protein contains six CCHC-type zinc fingers, and is thus thought to function as a transcription factor. [provided by RefSeq, May 2010]

ZCCHC13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07359865).

BS2

High Hemizygotes in GnomAdExome4 at 43 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203303.3. 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
	ZCCHC13	NM_203303.3	MANE Select	c.263G>A	p.Arg88His	missense	Exon 1 of 1	NP_976048.1	Q8WW36

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC13	ENST00000339534.4	TSL:6 MANE Select	c.263G>A	p.Arg88His	missense	Exon 1 of 1	ENSP00000345633.2	Q8WW36

Frequencies

GnomAD3 genomes

AF:

0.0000799

AC:

AN:

112613

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:

0.000560

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000131

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000818

AC:

AN:

183427

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

154

AN:

1098253

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

363607

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.000662

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000144

AC:

121

AN:

842137

Other (OTH)

AF:

0.000174

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000799

AC:

AN:

112613

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34755

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31033

American (AMR)

AF:

0.00

AC:

AN:

10686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.000560

AC:

AN:

3572

South Asian (SAS)

AF:

0.00

AC:

AN:

2722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6191

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000131

AC:

AN:

53311

Other (OTH)

AF:

0.00

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000142

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

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

0.085

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0047

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.51

M_CAP

Benign

0.0018

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

5.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.42

REVEL

Benign

0.18

Sift

Uncertain

0.025

Sift4G

Uncertain

0.048

Polyphen

0.30

Vest4

0.084

MVP

0.067

MPC

0.44

ClinPred

0.14

GERP RS

3.1

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.11

gMVP

0.26

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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