6-29673737-C-T

Position:

chr6-29673737-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/17 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 submissions are: {Uncertain_significance=1, Benign=5}. Variant chr6-29673737-C-T is described in Lovd as [Benign]. Variant chr6-29673737-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2091 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFP57	NM_001109809.5 linkuse as main transcript	c.374G>A	p.Arg125Gln	missense_variant	5/5	ENST00000376883.2	NP_001103279.2
ZFP57	NM_001366333.2 linkuse as main transcript	c.158G>A	p.Arg53Gln	missense_variant	4/4		NP_001353262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFP57	ENST00000376883.2 linkuse as main transcript	c.374G>A	p.Arg125Gln	missense_variant	5/5	5	NM_001109809.5	ENSP00000366080	P1	Q9NU63-3
ZFP57	ENST00000488757.6 linkuse as main transcript	c.158G>A	p.Arg53Gln	missense_variant	4/4	1		ENSP00000418259

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

GnomAD3 exomes

AF:

0.0165

AC:

3988

AN:

241450

Hom.:

AF XY:

0.0177

AC XY:

2342

AN XY:

132472

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 SAS exome

AF:

0.0340

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

Gnomad4 AFR exome

AF:

0.00445

Gnomad4 AMR exome

AF:

0.00420

Gnomad4 ASJ exome

AF:

0.00566

Gnomad4 EAS exome

AF:

0.000882

Gnomad4 SAS exome

AF:

0.0349

Gnomad4 FIN exome

AF:

0.0384

Gnomad4 NFE exome

AF:

0.0162

Gnomad4 OTH exome

AF:

0.0135

GnomAD4 genome

AF:

0.0137

AC:

2091

AN:

152320

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1073

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00601

Gnomad4 AMR

AF:

0.00634

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.00578

Gnomad4 SAS

AF:

0.0282

Gnomad4 FIN

AF:

0.0334

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0136

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	- -

Transitory neonatal diabetes mellitus

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 04, 2013

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Dec 21, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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

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

MutationTaster

Benign

1.0

N;N;N

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

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

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