X-104114941-A-C

Variant names:

Variant summary

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

The NM_001143978.3(ZCCHC18):c.830A>C(p.Glu277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000343 in 1,196,605 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000036 ( 0 hom. 15 hem. )

Consequence

ZCCHC18
NM_001143978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

Publications

0 publications found

Variant links:

Genes affected

ZCCHC18 (HGNC:32459): (zinc finger CCHC-type containing 18) Predicted to enable metal ion binding activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC18 links:

SLC25A53 (HGNC:31894): (solute carrier family 25 member 53) Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC25A53 links:

Genome browser will be placed here

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=0.11086443).

BS2

High Hemizygotes in GnomAdExome4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC18	NM_001143978.3 link	c.830A>C	p.Glu277Ala	missense_variant	Exon 3 of 3	ENST00000650639.1	NP_001137450.1	P0CG32
SLC25A53	NM_001012755.5 link	c.-31-9653T>G		intron_variant	Intron 1 of 1	ENST00000594199.3	NP_001012773.2	Q5H9E4
ZCCHC18	XM_011531012.4 link	c.830A>C	p.Glu277Ala	missense_variant	Exon 3 of 3		XP_011529314.1	P0CG32
ZCCHC18	NR_026694.3 link	n.672-311A>C		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZCCHC18	ENST00000650639.1 link	c.830A>C	p.Glu277Ala	missense_variant	Exon 3 of 3		NM_001143978.3	ENSP00000498828.1	P0CG32
SLC25A53	ENST00000594199.3 link	c.-31-9653T>G		intron_variant	Intron 1 of 1	1	NM_001012755.5	ENSP00000468980.1	Q5H9E4
ZCCHC18	ENST00000537356.3 link	c.830A>C	p.Glu277Ala	missense_variant	Exon 2 of 2	5		ENSP00000473824.1	P0CG32
ZCCHC18	ENST00000422784.5 link	n.651-311A>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111901

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000943

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000143

AC:

AN:

153835

AF XY:

0.000189

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000529

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000152

Gnomad OTH exome

AF:

0.000752

GnomAD4 exome

AF:

0.0000360

AC:

AN:

1084704

Hom.:

Cov.:

AF XY:

0.0000424

AC XY:

AN XY:

353926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26074

American (AMR)

AF:

0.000391

AC:

AN:

33224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19096

East Asian (EAS)

AF:

0.00

AC:

AN:

29598

South Asian (SAS)

AF:

0.000249

AC:

AN:

52265

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39711

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.00000599

AC:

AN:

834992

Other (OTH)

AF:

0.0000658

AC:

AN:

45624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000179

AC:

AN:

111901

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34051

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30748

American (AMR)

AF:

0.0000943

AC:

AN:

10603

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3564

South Asian (SAS)

AF:

0.00

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53180

Other (OTH)

AF:

0.00

AC:

AN:

1500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.830A>C (p.E277A) alteration is located in exon 3 (coding exon 1) of the ZCCHC18 gene. This alteration results from a A to C substitution at nucleotide position 830, causing the glutamic acid (E) at amino acid position 277 to be replaced by an alanine (A). 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

0.22

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.60

CADD

Uncertain

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.039

T;T

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.81

.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.11

T;T

MutationAssessor

Benign

1.8

L;L

PhyloP100

3.0

PrimateAI

Benign

0.47

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.12

MVP

0.25

MPC

0.70

GERP RS

3.6

Varity_R

0.18

gMVP

0.53

Mutation Taster

=78/22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over