6-29673174-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.972

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 -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 GnomAd at 1464 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00962 AC: 1464 AN: 152114 Hom.: 15 Cov.: 32

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.: 24 AF XY: 0.0111 AC XY: 1487 AN XY: 133892

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.: 31 AF XY: 0.0122 AC XY: 8894 AN XY: 726702

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.: 15 Cov.: 32 AF XY: 0.00919 AC XY: 684 AN XY: 74440

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.: 21

Bravo AF: 0.00812

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00372 AC: 9

ESP6500EA AF: 0.0143 AC: 72

ExAC AF: 0.0119 AC: 1388

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0144

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.95
Dann	Benign	0.69
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.49	T;T;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.19	T
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	T
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

Other links and lift over

dbSNP: rs61730327; hg19: chr6-29640951;