Genetic Variant ZNF677:p.Arg499His (chr19-53237231-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_182609.4(ZNF677):c.1496G>A(p.Arg499His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,340 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ZNF677
NM_182609.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.02

Variant links:

Genes affected

ZNF677 (HGNC:28730): (zinc finger protein 677) 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]

ZNF677 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14013118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF677	NM_182609.4 link	c.1496G>A	p.Arg499His	missense_variant	Exon 5 of 5	ENST00000598513.6	NP_872415.1	Q86XU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF677	ENST00000598513.6 link	c.1496G>A	p.Arg499His	missense_variant	Exon 5 of 5	1	NM_182609.4	ENSP00000469391.1		Q86XU0
ZNF677	ENST00000333952.8 link	c.1496G>A	p.Arg499His	missense_variant	Exon 3 of 3	2		ENSP00000334394.4		Q86XU0

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.00

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250778

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00000882

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460516

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726604

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151824

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000480

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1496G>A (p.R499H) alteration is located in exon 5 (coding exon 3) of the ZNF677 gene. This alteration results from a G to A substitution at nucleotide position 1496, causing the arginine (R) at amino acid position 499 to be replaced by a histidine (H). 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

0.18

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.3

DANN

Benign

0.74

DEOGEN2

Benign

0.038

T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.00073

LIST_S2

Benign

0.41

.;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.66

.;N

REVEL

Benign

0.13

Sift

Benign

0.59

.;T

Sift4G

Benign

0.58

T;T

Polyphen

1.0

D;D

Vest4

0.20

MutPred

0.50

Loss of MoRF binding (P = 0.0545);Loss of MoRF binding (P = 0.0545);

MVP

0.56

MPC

0.050

ClinPred

0.12

GERP RS

2.2

Varity_R

0.028

gMVP

0.023

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