Variant chr16-31076755-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014699.4(ZNF646):c.431C>A(p.Thr144Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,502 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZNF646
NM_014699.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.341

Variant links:

Genes affected

ZNF646 (HGNC:29004): (zinc finger protein 646) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF646 links:

ZNF646 (HGNC:):

ZNF646 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056797296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF646	NM_014699.4 linkuse as main transcript	c.431C>A	p.Thr144Lys	missense_variant	2/3	ENST00000300850.5	NP_055514.3	O15015-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF646	ENST00000300850.5 linkuse as main transcript	c.431C>A	p.Thr144Lys	missense_variant	2/3	1	NM_014699.4	ENSP00000300850.5	O15015-2
ZNF646	ENST00000394979.2 linkuse as main transcript	c.431C>A	p.Thr144Lys	missense_variant	1/1	6		ENSP00000378429.2	O15015-1
ZNF646	ENST00000428260.1 linkuse as main transcript	c.431C>A	p.Thr144Lys	missense_variant	2/2	3		ENSP00000391271.1	C9J3L0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251198

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461502

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.431C>A (p.T144K) alteration is located in exon 2 (coding exon 1) of the ZNF646 gene. This alteration results from a C to A substitution at nucleotide position 431, causing the threonine (T) at amino acid position 144 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

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

5.6

DANN

Benign

0.88

DEOGEN2

Benign

0.032

.;T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.61

T;T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.057

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

L;.;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.043

Sift

Benign

0.69

T;D;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.28

B;.;.

Vest4

0.11

MutPred

0.30

Gain of ubiquitination at T144 (P = 0.0114);Gain of ubiquitination at T144 (P = 0.0114);Gain of ubiquitination at T144 (P = 0.0114);

MVP

0.37

MPC

0.26

ClinPred

0.11

GERP RS

1.6

Varity_R

0.054

gMVP

0.47

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