chr6-29672639-G-C

Position:

• chr6-29672639-G-C

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.1472C>G​(p.Thr491Ser) 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 1,611,308 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:4
• Conservation: PhyloP100: 0.434

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=0.0045357347).
• BP6: Variant 6-29672639-G-C is Benign according to our data. Variant chr6-29672639-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 356211.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr6-29672639-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0022 (335/152254) while in subpopulation AMR AF= 0.00642 (98/15276). AF 95% confidence interval is 0.00539. There are 8 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 335 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFP57	NM_001109809.5	c.1472C>G	p.Thr491Ser	missense_variant	5/5	ENST00000376883.2
ZFP57	NM_001366333.2	c.1256C>G	p.Thr419Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFP57	ENST00000376883.2	c.1472C>G	p.Thr491Ser	missense_variant	5/5	5	NM_001109809.5	P1
ZFP57	ENST00000488757.6	c.1256C>G	p.Thr419Ser	missense_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152136 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00153 AC: 375 AN: 244546 Hom.: 2 AF XY: 0.00158 AC XY: 212 AN XY: 133844

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00258

Gnomad SAS exome AF: 0.000329

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00126 AC: 1834 AN: 1459054 Hom.: 5 Cov.: 31 AF XY: 0.00127 AC XY: 924 AN XY: 725444

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.000192

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: 0.00220 AC: 335 AN: 152254 Hom.: 8 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74424

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00642

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.00230

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00118 AC: 3

ESP6500EA AF: 0.00195 AC: 10

ExAC AF: 0.00171 AC: 199

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:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ZFP57: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.1472C>G (p.T491S) alteration is located in exon 4 (coding exon 4) of the ZFP57 gene. This alteration results from a C to G substitution at nucleotide position 1472, causing the threonine (T) at amino acid position 491 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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 -

Diabetes mellitus, transient neonatal, 1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	0.10
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.2
DANN	Benign	0.46
DEOGEN2	Benign	0.030	.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.43	T;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.0	N;N;.
REVEL	Benign	0.024
Sift	Benign	0.71	T;T;.
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.10
MutPred		0.40		Gain of disorder (P = 0.0423);.;.;
MVP		0.15
MPC		0.38
ClinPred		0.00054	T
GERP RS		2.1
Varity_R		0.030
gMVP		0.038

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: rs184974475; hg19: chr6-29640416;