6-29673078-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001109809.5(ZFP57):c.1033G>C(p.Ala345Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,612,966 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0022 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: ZFP57 NM_001109809.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.00300

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032929778).
• BP6: Variant 6-29673078-C-G is Benign according to our data. Variant chr6-29673078-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 904449.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}. Variant chr6-29673078-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00221 (337/152194) while in subpopulation AMR AF= 0.00641 (98/15286). AF 95% confidence interval is 0.00538. There are 8 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFP57	NM_001109809.5	c.1033G>C	p.Ala345Pro	missense_variant	5/5	ENST00000376883.2
ZFP57	NM_001366333.2	c.817G>C	p.Ala273Pro	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFP57	ENST00000376883.2	c.1033G>C	p.Ala345Pro	missense_variant	5/5	5	NM_001109809.5	P1
ZFP57	ENST00000488757.6	c.817G>C	p.Ala273Pro	missense_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152076 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00154 AC: 376 AN: 244622 Hom.: 2 AF XY: 0.00158 AC XY: 212 AN XY: 133886

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00258

Gnomad SAS exome AF: 0.000329

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00126 AC: 1838 AN: 1460772 Hom.: 5 Cov.: 31 AF XY: 0.00128 AC XY: 927 AN XY: 726702

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0000956

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152194 Hom.: 8 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74398

Gnomad4 AFR AF: 0.00222

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00206 Hom.: 1

Bravo AF: 0.00232

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00165 AC: 4

ESP6500EA AF: 0.00198 AC: 10

ExAC AF: 0.00174 AC: 203

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Diabetes mellitus, transient neonatal, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 01, 2019

ACMG criteria: BP4 (Revel score 0.024 + 9 predictors) =VUS Notes: PMID: 23748067 reported a Turkish patient with three novel homozygous ZFP57 variant, one is A345P (called A325P), the other is T159S(called T139S). But the patient has another homozygous S252P, which is more likely to be the cause since it's conserved across species. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

ZFP57-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.3
Dann	Benign	0.75
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.24	T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0033	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.32	N;N;.
REVEL	Benign	0.032
Sift	Benign	0.37	T;T;.
Sift4G	Benign	0.60	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.059
MVP		0.12
MPC		0.55
ClinPred		0.0011	T
GERP RS		-0.054
Varity_R		0.071
gMVP		0.15

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: rs200537697; hg19: chr6-29640855;