6-29676891-C-T

Position:

• chr6-29676891-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001109809.5(ZFP57):​c.113G>A​(p.Arg38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,102 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (141 hom.)
• Consequence: ZFP57 NM_001109809.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 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 -9 ACMG points.

• BP6: Variant 6-29676891-C-T is Benign according to our data. Variant chr6-29676891-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130770.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr6-29676891-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFP57	NM_001109809.5	c.113G>A	p.Arg38Gln	missense_variant	2/5	ENST00000376883.2	NP_001103279.2
ZFP57	NM_001366333.2	c.-93-832G>A		intron_variant			NP_001353262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFP57	ENST00000376883.2	c.113G>A	p.Arg38Gln	missense_variant	2/5	5	NM_001109809.5	ENSP00000366080.2
ZFP57	ENST00000488757.6	c.-93-832G>A		intron_variant		1		ENSP00000418259.2

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152198 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0252

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00107 AC: 267 AN: 249380 Hom.: 9 AF XY: 0.00113 AC XY: 153 AN XY: 135332

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00623

Gnomad SAS exome AF: 0.00274

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.00216 AC: 3154 AN: 1461786 Hom.: 141 Cov.: 32 AF XY: 0.00224 AC XY: 1628 AN XY: 727198

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0612

Gnomad4 SAS exome AF: 0.00278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152316 Hom.: 6 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74482

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0253

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000666 Hom.: 1

Bravo AF: 0.000514

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00138 AC: 167

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	- -

Diabetes mellitus, transient neonatal, 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Benign	0.97
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.35	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.30	N;N
REVEL	Benign	0.058
Sift	Benign	0.34	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0010	B;B
Vest4		0.25
MVP		0.16
MPC		0.51
ClinPred		0.012	T
GERP RS		2.3
gMVP		0.025

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142917604; hg19: chr6-29644668;