rs61730326

Positions:

• chr6-29673025-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001109809.5(ZFP57):​c.1086T>C​(p.Thr362=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,613,078 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (22 hom.)
• Consequence: ZFP57 NM_001109809.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.873

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-29673025-A-G is Benign according to our data. Variant chr6-29673025-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-29673025-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.873 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00527 (803/152306) while in subpopulation AFR AF= 0.00953 (396/41574). AF 95% confidence interval is 0.00875. There are 3 homozygotes in gnomad4. There are 379 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 803 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFP57	NM_001109809.5	c.1086T>C	p.Thr362=	synonymous_variant	5/5	ENST00000376883.2	NP_001103279.2
ZFP57	NM_001366333.2	c.870T>C	p.Thr290=	synonymous_variant	4/4		NP_001353262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFP57	ENST00000376883.2	c.1086T>C	p.Thr362=	synonymous_variant	5/5	5	NM_001109809.5	ENSP00000366080	P1
ZFP57	ENST00000488757.6	c.870T>C	p.Thr290=	synonymous_variant	4/4	1		ENSP00000418259

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 795 AN: 152188 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00936

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00360 AC: 881 AN: 244666 Hom.: 6 AF XY: 0.00364 AC XY: 487 AN XY: 133900

Gnomad AFR exome AF: 0.00844

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00135

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00368

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.00337 AC: 4921 AN: 1460772 Hom.: 22 Cov.: 31 AF XY: 0.00338 AC XY: 2457 AN XY: 726702

Gnomad4 AFR exome AF: 0.00917

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.000325

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152306 Hom.: 3 Cov.: 32 AF XY: 0.00509 AC XY: 379 AN XY: 74468

Gnomad4 AFR AF: 0.00953

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00545 Hom.: 3

Bravo AF: 0.00588

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00498

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ZFP57: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Diabetes mellitus, transient neonatal, 1 Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 16, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 21, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.68
DANN	Benign	0.57

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

Other links and lift over

dbSNP: rs61730326; hg19: chr6-29640802;