Genetic Variant ZNF439:p.Met298Thr (chr19-11867947-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001348719.2(ZNF439):c.893T>C(p.Met298Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ZNF439
NM_001348719.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0420

Variant links:

Genes affected

ZNF439 (HGNC:20873): (zinc finger protein 439) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA 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]

ZNF439 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009378701).

BP6

Variant 19-11867947-T-C is Benign according to our data. Variant chr19-11867947-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2612519.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF439	NM_001348719.2 link	c.893T>C	p.Met298Thr	missense_variant	Exon 4 of 4	ENST00000682736.1	NP_001335648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF439	ENST00000682736.1 link	c.893T>C	p.Met298Thr	missense_variant	Exon 4 of 4		NM_001348719.2	ENSP00000506930.1	A0A804HI69
ZNF439	ENST00000304030.2 link	c.878T>C	p.Met293Thr	missense_variant	Exon 3 of 3	1		ENSP00000305077.2	Q8NDP4
ZNF439	ENST00000455282.1 link	c.470T>C	p.Met157Thr	missense_variant	Exon 3 of 3	1		ENSP00000395632.1	A0A0C4DG37
ZNF439	ENST00000592534.1 link	n.120-15604T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 19, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.0050

DANN

Benign

0.13

DEOGEN2

Benign

0.0051

.;T

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.000090

LIST_S2

Benign

0.027

T;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.0094

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.8

.;N

PrimateAI

Benign

0.24

PROVEAN

Benign

4.5

N;N

REVEL

Benign

0.021

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.081

MutPred

0.31

.;Gain of phosphorylation at M293 (P = 0.017);

MVP

0.099

MPC

0.057

ClinPred

0.041

GERP RS

-1.1

Varity_R

0.028

gMVP

0.0075

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over