Genetic Variant NM_032924.5:c.1310C>A (chr7-100071174-G-T) – 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.1310C>A(p.Thr437Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T437M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZNF3
NM_032924.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.222

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=0.11023539).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF3	NM_032924.5 link	c.1310C>A	p.Thr437Lys	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.1310C>A	p.Thr437Lys	missense_variant	Exon 6 of 6	1	NM_032924.5	ENSP00000299667.4		P17036-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1452962

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722138

African (AFR)

AF:

0.00

AC:

AN:

33094

American (AMR)

AF:

0.00

AC:

AN:

43400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25624

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

85318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107154

Other (OTH)

AF:

0.00

AC:

AN:

59912

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1310C>A (p.T437K) alteration is located in exon 6 (coding exon 4) of the ZNF3 gene. This alteration results from a C to A substitution at nucleotide position 1310, causing the threonine (T) at amino acid position 437 to be replaced by a lysine (K). 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

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.018

T;T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.0058

LIST_S2

Benign

0.079

.;T;.

M_CAP

Benign

0.0083

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;L;L

PhyloP100

0.22

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.011

D;D;D

Sift4G

Benign

0.26

T;T;T

Polyphen

0.18

B;B;B

Vest4

0.27

MutPred

0.47

Gain of ubiquitination at T437 (P = 0.0162);Gain of ubiquitination at T437 (P = 0.0162);Gain of ubiquitination at T437 (P = 0.0162);

MVP

0.34

MPC

0.37

ClinPred

0.21

GERP RS

4.7

Varity_R

0.13

gMVP

0.42

Mutation Taster

=89/11

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over