chr6-29673174-T-C

Position:

chr6-29673174-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001109809.5(ZFP57):c.937A>G(p.Arg313Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,002 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 15 hom., cov: 32)

Exomes 𝑓: 0.012 ( 153 hom. )

Consequence

ZFP57
NM_001109809.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.972

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003173411).

BP6

Variant 6-29673174-T-C is Benign according to our data. Variant chr6-29673174-T-C is described in ClinVar as [Benign]. Clinvar id is 904450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-29673174-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00962 (1465/152232) while in subpopulation NFE AF= 0.0163 (1110/67996). AF 95% confidence interval is 0.0155. There are 15 homozygotes in gnomad4. There are 684 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1465 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFP57	NM_001109809.5 linkuse as main transcript	c.937A>G	p.Arg313Gly	missense_variant	5/5	ENST00000376883.2
ZFP57	NM_001366333.2 linkuse as main transcript	c.721A>G	p.Arg241Gly	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFP57	ENST00000376883.2 linkuse as main transcript	c.937A>G	p.Arg313Gly	missense_variant	5/5	5	NM_001109809.5	P1	Q9NU63-3
ZFP57	ENST00000488757.6 linkuse as main transcript	c.721A>G	p.Arg241Gly	missense_variant	4/4	1

Frequencies

GnomAD3 genomes

AF:

0.00962

AC:

1464

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.0111

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.0108

AC:

2641

AN:

244622

Hom.:

AF XY:

0.0111

AC XY:

1487

AN XY:

133892

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.00230

Gnomad ASJ exome

AF:

0.00100

Gnomad EAS exome

AF:

0.0000560

Gnomad SAS exome

AF:

0.0113

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0169

Gnomad OTH exome

AF:

0.00833

GnomAD4 exome

AF:

0.0125

AC:

18199

AN:

1460770

Hom.:

153

Cov.:

AF XY:

0.0122

AC XY:

8894

AN XY:

726702

show subpopulations

Gnomad4 AFR exome

AF:

0.00173

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0112

Gnomad4 FIN exome

AF:

0.0113

Gnomad4 NFE exome

AF:

0.0143

Gnomad4 OTH exome

AF:

0.00760

GnomAD4 genome

AF:

0.00962

AC:

1465

AN:

152232

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

684

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00301

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0120

Gnomad4 FIN

AF:

0.0111

Gnomad4 NFE

AF:

0.0163

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.0130

Hom.:

Bravo

AF:

0.00812

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00372

AC:

ESP6500EA

AF:

0.0143

AC:

ExAC

AF:

0.0119

AC:

1388

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0134

EpiControl

AF:

0.0144

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diabetes mellitus, transient neonatal, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Nov 21, 2018

ACMG criteria: BP4 (8 predictors, REVEL 0.024), BS1 (1.7% in ExAC European pop.), BS2 (27 homozygotes in gnomAD)= benign -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.95

DANN

Benign

0.69

DEOGEN2

Benign

0.12

.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.49

T;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.3

N;N;.

REVEL

Benign

0.024

Sift

Benign

0.24

T;T;.

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.022

MPC

0.54

ClinPred

0.00027

GERP RS

-2.0

Varity_R

0.060

gMVP

0.17

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