Genetic Variant NM_032924.5:c.1337C>T (chr7-100071147-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032924.5(ZNF3):c.1337C>T(p.Thr446Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,580,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ZNF3
NM_032924.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

Publications

1 publications found

Variant links:

Genes affected

ZNF3 (HGNC:13089): (zinc finger protein 3) Enables identical protein binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2580381).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF3	NM_032924.5 link	c.1337C>T	p.Thr446Met	missense_variant	Exon 6 of 6	ENST00000299667.9	NP_116313.3	P17036-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF3	ENST00000299667.9 link	c.1337C>T	p.Thr446Met	missense_variant	Exon 6 of 6	1	NM_032924.5	ENSP00000299667.4		P17036-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000220

AC:

AN:

227552

AF XY:

0.0000244

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.0000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000191

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1428778

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

707260

show subpopulations

African (AFR)

AF:

0.0000925

AC:

AN:

32448

American (AMR)

AF:

0.0000244

AC:

AN:

41024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23862

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39384

South Asian (SAS)

AF:

0.00

AC:

AN:

80892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52384

Middle Eastern (MID)

AF:

0.000199

AC:

AN:

5024

European-Non Finnish (NFE)

AF:

0.00000731

AC:

AN:

1094868

Other (OTH)

AF:

0.0000170

AC:

AN:

58892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41438

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000604

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000239

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1337C>T (p.T446M) alteration is located in exon 6 (coding exon 4) of the ZNF3 gene. This alteration results from a C to T substitution at nucleotide position 1337, causing the threonine (T) at amino acid position 446 to be replaced by a methionine (M). 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

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

T;T;T

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.83

.;T;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

N;N;N

PhyloP100

2.6

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.17

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.28

MVP

0.59

MPC

0.38

ClinPred

0.17

GERP RS

4.7

Varity_R

0.12

gMVP

0.27

Mutation Taster

=79/21

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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NM_032924.5:c.1337C>T

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