Variant 19-57754093-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_173632.4(ZNF776):c.963A>C(p.Glu321Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,606,846 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

ZNF776
NM_173632.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.46

Variant links:

Genes affected

ZNF776 (HGNC:26765): (zinc finger protein 776) 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 by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF776 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017343909).

BS2

High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF776	NM_173632.4 linkuse as main transcript	c.963A>C	p.Glu321Asp	missense_variant	3/3	ENST00000317178.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ZNF776	ENST00000317178.10 linkuse as main transcript	c.963A>C	p.Glu321Asp	missense_variant	3/3	1	NM_173632.4	P1
ZNF776	ENST00000451849.1 linkuse as main transcript	c.109-2779A>C		intron_variant		3
ZNF776	ENST00000489376.1 linkuse as main transcript	n.50A>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.000124

AC:

AN:

144932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000516

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000819

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000223

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00102

GnomAD3 exomes

AF:

0.000390

AC:

AN:

251432

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00246

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:

0.0000967

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000135

AC:

198

AN:

1461778

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00255

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000648

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000124

AC:

AN:

145068

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

70846

show subpopulations

Gnomad4 AFR

AF:

0.0000514

Gnomad4 AMR

AF:

0.000818

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000223

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000152

Gnomad4 OTH

AF:

0.00100

Bravo

AF:

0.000204

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

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

Aug 02, 2022

The c.963A>C (p.E321D) alteration is located in exon 3 (coding exon 3) of the ZNF776 gene. This alteration results from a A to C substitution at nucleotide position 963, causing the glutamic acid (E) at amino acid position 321 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

Benign

0.34

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.36

M_CAP

Benign

0.0020

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.72

MutationTaster

Benign

1.0

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.071

Sift

Uncertain

0.013

Sift4G

Uncertain

0.060

Polyphen

0.99

Vest4

0.094

MutPred

0.37

Gain of phosphorylation at Y320 (P = 0.1649);

MVP

0.38

MPC

0.38

ClinPred

0.12

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

Varity_R

0.16

gMVP

0.032

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