6-29673737-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001109809.5(ZFP57):c.374G>A(p.Arg125Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,016 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.014 ( 21 hom., cov: 32)

Exomes 𝑓: 0.017 ( 298 hom. )

Consequence

ZFP57
NM_001109809.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -2.39

Publications

6 publications found

Variant links:

Genes affected

ZFP57 (HGNC:18791): (ZFP57 zinc finger protein) The protein encoded by this gene is a zinc finger protein containing a KRAB domain. Studies in mouse suggest that this protein may function as a transcriptional repressor. Mutations in this gene have been associated with transient neonatal diabetes mellitus type 1 (TNDM1).[provided by RefSeq, Sep 2009]

ZFP57 Gene-Disease associations (from GenCC):

diabetes mellitus, transient neonatal, 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
transient neonatal diabetes mellitus
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ZFP57 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002755016).

BP6

Variant 6-29673737-C-T is Benign according to our data. Variant chr6-29673737-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130774.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0137 (2091/152320) while in subpopulation SAS AF = 0.0282 (136/4826). AF 95% confidence interval is 0.0243. There are 21 homozygotes in GnomAd4. There are 1073 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP57	NM_001109809.5 link	c.374G>A	p.Arg125Gln	missense_variant	Exon 5 of 5	ENST00000376883.2	NP_001103279.2	Q9NU63-3A0A1U9X8V5B7ZW61
ZFP57	NM_001366333.2 link	c.158G>A	p.Arg53Gln	missense_variant	Exon 4 of 4		NP_001353262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP57	ENST00000376883.2 link	c.374G>A	p.Arg125Gln	missense_variant	Exon 5 of 5	5	NM_001109809.5	ENSP00000366080.2		Q9NU63-3
ZFP57	ENST00000488757.6 link	c.158G>A	p.Arg53Gln	missense_variant	Exon 4 of 4	1		ENSP00000418259.2		A0A7I2S1M6

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2090

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00598

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00576

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0334

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0165

AC:

3988

AN:

241450

AF XY:

0.0177

show subpopulations

Gnomad AFR exome

AF:

0.00554

Gnomad AMR exome

AF:

0.00416

Gnomad ASJ exome

AF:

0.00565

Gnomad EAS exome

AF:

0.00235

Gnomad FIN exome

AF:

0.0365

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.0167

AC:

24376

AN:

1460696

Hom.:

298

Cov.:

AF XY:

0.0173

AC XY:

12567

AN XY:

726676

show subpopulations

African (AFR)

AF:

0.00445

AC:

149

AN:

33480

American (AMR)

AF:

0.00420

AC:

188

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00566

AC:

148

AN:

26136

East Asian (EAS)

AF:

0.000882

AC:

AN:

39700

South Asian (SAS)

AF:

0.0349

AC:

3007

AN:

86258

European-Finnish (FIN)

AF:

0.0384

AC:

2005

AN:

52252

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0162

AC:

18007

AN:

1111992

Other (OTH)

AF:

0.0135

AC:

814

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

1393

2786

4180

5573

6966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0137

AC:

2091

AN:

152320

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1073

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00601

AC:

250

AN:

41570

American (AMR)

AF:

0.00634

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.00578

AC:

AN:

5194

South Asian (SAS)

AF:

0.0282

AC:

136

AN:

4826

European-Finnish (FIN)

AF:

0.0334

AC:

354

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1172

AN:

68028

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0141

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.0106

AC:

ESP6500EA

AF:

0.0141

AC:

ExAC

AF:

0.0175

AC:

2030

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Diabetes mellitus, transient neonatal, 1

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Transitory neonatal diabetes mellitus

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ZFP57 gene mutations are associated with neonatal diabetes, however the role of this particular variant (rs114591600) of ZFP57 gene remains uncertain and needs further clinical validation. -

not specified

Benign:1

Dec 04, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

Dec 21, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BP4 (REVEL 0.004, 10 predictors), BA1 (3.6% gnomAD EF, 3.3% SA, 1.7% ENF), BS2 (216 cases and 229 controls in type2diabetesgenetics.org)= benign -

not provided

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.024

(source)

DANN

Benign

0.69

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.53

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.90

PhyloP100

-2.4

PrimateAI

Benign

0.15

PROVEAN

Benign

0.57

N;N

REVEL

Benign

0.0040

Sift

Benign

0.71

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0020

B;B

Vest4

0.021

MPC

0.48

ClinPred

0.00040

GERP RS

-4.2

gMVP

0.093

Mutation Taster

=100/0

polymorphism (auto)

(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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6-29673737-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over