Variant 19-2933700-G-T 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_021217.3(ZNF77):c.1427C>A(p.Ala476Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000701 in 1,611,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A476T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 0 hom. )

Consequence

ZNF77
NM_021217.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0240

Variant links:

Genes affected

ZNF77 (HGNC:13150): (zinc finger protein 77) 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]

ZNF77 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=0.021636873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ZNF77	NM_021217.3 linkuse as main transcript	c.1427C>A	p.Ala476Asp	missense_variant	4/4	ENST00000314531.5
ZNF77	XM_047439170.1 linkuse as main transcript	c.1331C>A	p.Ala444Asp	missense_variant	4/4
ZNF77	XM_017027081.2 linkuse as main transcript	c.887C>A	p.Ala296Asp	missense_variant	3/3
ZNF77	XM_047439171.1 linkuse as main transcript	c.887C>A	p.Ala296Asp	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF77	ENST00000314531.5 linkuse as main transcript	c.1427C>A	p.Ala476Asp	missense_variant	4/4	1	NM_021217.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000823

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000531

AC:

133

AN:

250364

Hom.:

AF XY:

0.000503

AC XY:

AN XY:

135270

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.000954

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000726

AC:

1060

AN:

1459602

Hom.:

Cov.:

AF XY:

0.000750

AC XY:

544

AN XY:

725670

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.000868

Gnomad4 OTH exome

AF:

0.000697

GnomAD4 genome

AF:

0.000460

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000823

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000622

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000535

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000889

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

Jul 14, 2021

The c.1427C>A (p.A476D) alteration is located in exon 4 (coding exon 4) of the ZNF77 gene. This alteration results from a C to A substitution at nucleotide position 1427, causing the alanine (A) at amino acid position 476 to be replaced by an aspartic acid (D). 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

Pathogenic

0.60

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.71

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.057

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.000090

LIST_S2

Benign

0.080

M_CAP

Benign

0.0022

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.036

Sift

Benign

0.17

Sift4G

Benign

0.20

Polyphen

0.18

Vest4

0.11

MVP

0.29

MPC

0.075

ClinPred

0.027

GERP RS

-1.8

Varity_R

0.16

gMVP

0.042

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