6-29676948-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001109809.5(ZFP57):c.56G>A(p.Gly19Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,106 control chromosomes in the GnomAD database, including 1 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 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 1 hom. )

Consequence

ZFP57
NM_001109809.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.00300

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=0.024380386).

BP6

Variant 6-29676948-C-T is Benign according to our data. Variant chr6-29676948-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437334.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000164 (25/152234) while in subpopulation AFR AF= 0.000603 (25/41460). AF 95% confidence interval is 0.000419. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP57	NM_001109809.5 link	c.56G>A	p.Gly19Asp	missense_variant	Exon 2 of 5	ENST00000376883.2	NP_001103279.2	Q9NU63-3A0A1U9X8V5B7ZW61
ZFP57	NM_001366333.2 link	c.-93-889G>A		intron_variant	Intron 1 of 3		NP_001353262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP57	ENST00000376883.2 link	c.56G>A	p.Gly19Asp	missense_variant	Exon 2 of 5	5	NM_001109809.5	ENSP00000366080.2		Q9NU63-3
ZFP57	ENST00000488757.6 link	c.-93-889G>A		intron_variant	Intron 1 of 3	1		ENSP00000418259.2		A0A7I2S1M6

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249572

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135406

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000164

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000603

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000770

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 16, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Dec 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 19 of the ZFP57 protein (p.Gly19Asp). This variant is present in population databases (rs371500990, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with ZFP57-related conditions. ClinVar contains an entry for this variant (Variation ID: 437334). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Aug 05, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.67

DANN

Benign

0.74

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.34

M_CAP

Benign

0.0028

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.68

REVEL

Benign

0.018

Sift

Benign

0.77

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.13

MVP

0.11

MPC

0.55

ClinPred

0.0090

GERP RS

-3.8

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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