Genetic Variant NM_015117.3:c.2804C>G (chr8-143440052-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015117.3(ZC3H3):c.2804C>G(p.Thr935Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZC3H3
NM_015117.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.02

Publications

4 publications found

Variant links:

Genes affected

ZC3H3 (HGNC:28972): (zinc finger CCCH-type containing 3) Predicted to enable SMAD binding activity. Involved in regulation of mRNA polyadenylation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZC3H3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024352908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H3	NM_015117.3 link	c.2804C>G	p.Thr935Ser	missense_variant	Exon 11 of 12	ENST00000262577.6	NP_055932.2	Q8IXZ2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC3H3	ENST00000262577.6 link	c.2804C>G	p.Thr935Ser	missense_variant	Exon 11 of 12	1	NM_015117.3	ENSP00000262577.5		Q8IXZ2-1

Frequencies

GnomAD3 genomes

AF:

0.000599

AC:

AN:

148694

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000954

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000398

Gnomad ASJ

AF:

0.000593

Gnomad EAS

AF:

0.000391

Gnomad SAS

AF:

0.000214

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000584

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000121

AC:

AN:

165472

AF XY:

0.000166

show subpopulations

Gnomad AFR exome

AF:

0.000212

Gnomad AMR exome

AF:

0.0000897

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000200

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000301

AC:

413

AN:

1373034

Hom.:

Cov.:

AF XY:

0.000331

AC XY:

224

AN XY:

677506

show subpopulations

African (AFR)

AF:

0.000386

AC:

AN:

31086

American (AMR)

AF:

0.000182

AC:

AN:

32894

Ashkenazi Jewish (ASJ)

AF:

0.0000420

AC:

AN:

23802

East Asian (EAS)

AF:

0.0000530

AC:

AN:

37710

South Asian (SAS)

AF:

0.0000636

AC:

AN:

78556

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48608

Middle Eastern (MID)

AF:

0.000487

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.000336

AC:

356

AN:

1059598

Other (OTH)

AF:

0.000512

AC:

AN:

56674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.409

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000598

AC:

AN:

148810

Hom.:

Cov.:

AF XY:

0.000675

AC XY:

AN XY:

72624

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000951

AC:

AN:

39968

American (AMR)

AF:

0.000398

AC:

AN:

15084

Ashkenazi Jewish (ASJ)

AF:

0.000593

AC:

AN:

3374

East Asian (EAS)

AF:

0.000392

AC:

AN:

5104

South Asian (SAS)

AF:

0.000214

AC:

AN:

4670

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000584

AC:

AN:

66802

Other (OTH)

AF:

0.00

AC:

AN:

2070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000389

Hom.:

ExAC

AF:

0.000101

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2804C>G (p.T935S) alteration is located in exon 11 (coding exon 11) of the ZC3H3 gene. This alteration results from a C to G substitution at nucleotide position 2804, causing the threonine (T) at amino acid position 935 to be replaced by a serine (S). 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

0.085

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.099

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0039

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.35

M_CAP

Benign

0.0092

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

PhyloP100

-1.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.39

REVEL

Benign

0.017

Sift

Benign

0.24

Sift4G

Benign

1.0

Polyphen

0.012

Vest4

0.044

MutPred

0.087

Loss of glycosylation at T935 (P = 0.0767);

MVP

0.043

ClinPred

0.0062

GERP RS

-0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.049

gMVP

0.12

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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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NM_015117.3:c.2804C>G

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