Genetic Variant ZNF276:p.Ser35Phe (chr16-89721744-C-T) – 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_001113525.2(ZNF276):c.104C>T(p.Ser35Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000854 in 1,171,152 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: 34)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

ZNF276
NM_001113525.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0470

Publications

1 publications found

Variant links:

Genes affected

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ZNF276 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=0.06282523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF276	NM_001113525.2 link	c.104C>T	p.Ser35Phe	missense_variant	Exon 1 of 11	ENST00000443381.7	NP_001106997.1	Q8N554-1I6L9I3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF276	ENST00000443381.7 link	c.104C>T	p.Ser35Phe	missense_variant	Exon 1 of 11	1	NM_001113525.2	ENSP00000415836.2		Q8N554-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000217

AC:

AN:

4614

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.54e-7

AC:

AN:

1171152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

566646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23444

American (AMR)

AF:

0.00

AC:

AN:

9646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16090

East Asian (EAS)

AF:

0.00

AC:

AN:

26742

South Asian (SAS)

AF:

0.00

AC:

AN:

46682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3378

European-Non Finnish (NFE)

AF:

0.00000103

AC:

AN:

971066

Other (OTH)

AF:

0.00

AC:

AN:

47244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.104C>T (p.S35F) alteration is located in exon 1 (coding exon 1) of the ZNF276 gene. This alteration results from a C to T substitution at nucleotide position 104, causing the serine (S) at amino acid position 35 to be replaced by a phenylalanine (F). 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

-0.56

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.048

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.45

M_CAP

Benign

0.018

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.047

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.48

REVEL

Benign

0.063

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

0.12

Vest4

0.14

MutPred

0.20

Loss of phosphorylation at S35 (P = 0.0057);

MVP

0.030

MPC

0.087

ClinPred

0.081

GERP RS

2.9

PromoterAI

0.0026

Neutral

(source)

Varity_R

0.096

gMVP

0.076

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over