Genetic Variant NM_032494.3:c.506A>G (chr2-112234235-T-C) – 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_032494.3(ZC3H8):c.506A>G(p.Asp169Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,436,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ZC3H8
NM_032494.3 missense, splice_region

Scores

Splicing: ADA: 0.0001312

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.605

Publications

1 publications found

Variant links:

Genes affected

ZC3H8 (HGNC:30941): (zinc finger CCCH-type containing 8) Enables RNA binding activity. Involved in several processes, including positive regulation of thymocyte apoptotic process; regulation of transcription, DNA-templated; and snRNA transcription. Located in Cajal body; histone locus body; and transcriptionally active chromatin. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ZC3H8 links:

FBLN7 (HGNC:26740): (fibulin 7) Predicted to enable calcium ion binding activity; heparan sulfate proteoglycan binding activity; and heparin binding activity. Predicted to be involved in cell adhesion. Predicted to act upstream of or within positive regulation of biomineralization. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

FBLN7 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=0.062079072).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032494.3. 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
	ZC3H8	NM_032494.3	MANE Select	c.506A>G	p.Asp169Gly	missense splice_region	Exon 5 of 9	NP_115883.2	Q8N5P1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZC3H8	ENST00000409573.7	TSL:5 MANE Select	c.506A>G	p.Asp169Gly	missense splice_region	Exon 5 of 9	ENSP00000386488.1	Q8N5P1
ZC3H8	ENST00000866700.1		c.506A>G	p.Asp169Gly	missense splice_region	Exon 5 of 9	ENSP00000536759.1
ZC3H8	ENST00000866701.1		c.506A>G	p.Asp169Gly	missense splice_region	Exon 5 of 8	ENSP00000536760.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000896

AC:

AN:

223320

AF XY:

0.00000825

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:

0.0000192

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1436460

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

714092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32076

American (AMR)

AF:

0.00

AC:

AN:

38754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25576

East Asian (EAS)

AF:

0.00

AC:

AN:

39340

South Asian (SAS)

AF:

0.00

AC:

AN:

80710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

1101878

Other (OTH)

AF:

0.0000336

AC:

AN:

59508

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

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:

0.0000156

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000166

AC:

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

0.063

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0078

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.61

M_CAP

Benign

0.0035

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.60

PrimateAI

Benign

0.26

PROVEAN

Benign

0.30

REVEL

Benign

0.083

Sift

Benign

0.16

Sift4G

Benign

0.54

Polyphen

0.0010

Vest4

0.040

MVP

0.12

MPC

0.21

ClinPred

0.088

GERP RS

-0.48

Varity_R

0.043

gMVP

0.37

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.030

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over