dbSNP rs956826116: ZNF676:p.Ser543Arg (chr19-22180090-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001001411.3(ZNF676):c.1627A>C(p.Ser543Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ZNF676
NM_001001411.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.31

Variant links:

Genes affected

ZNF676 (HGNC:20429): (zinc finger protein 676) 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]

ZNF676 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05588883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF676	NM_001001411.3 link	c.1627A>C	p.Ser543Arg	missense_variant	Exon 3 of 3	ENST00000397121.3	NP_001001411.2	Q8N7Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF676	ENST00000397121.3 link	c.1627A>C	p.Ser543Arg	missense_variant	Exon 3 of 3	2	NM_001001411.3	ENSP00000380310.1		Q8N7Q3
ZNF676	ENST00000650058.1 link	c.1723A>C	p.Ser575Arg	missense_variant	Exon 4 of 4			ENSP00000497897.1		A0A3B3ITU2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247628

AF XY:

0.00000744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461584

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111852

Other (OTH)

AF:

0.000116

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 25, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1627A>C (p.S543R) alteration is located in exon 3 (coding exon 3) of the ZNF676 gene. This alteration results from a A to C substitution at nucleotide position 1627, causing the serine (S) at amino acid position 543 to be replaced by an arginine (R). 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.1

(source)

DANN

Benign

0.085

DEOGEN2

Benign

0.0028

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.039

.;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.47

N;.

PhyloP100

-1.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.83

N;.

REVEL

Benign

0.073

Sift

Benign

0.35

T;.

Sift4G

Benign

0.45

T;.

Polyphen

0.96

D;.

Vest4

0.097

MutPred

0.38

Loss of ubiquitination at K540 (P = 0.0167);.;

MVP

0.095

MPC

0.11

ClinPred

0.091

GERP RS

-1.6

Varity_R

0.053

gMVP

0.0068

Mutation Taster

=100/0

polymorphism

(source)

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

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rs956826116

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over