6-29672993-G-C

Variant names:

• chr6-29672993-G-C
• rs193232883
• NM_001109809.5:c.1118C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001109809.5(ZFP57):​c.1118C>G​(p.Ser373Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000678 in 1,613,098 control chromosomes in the GnomAD database, including 12 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 0.00050 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (11 hom.)
• Consequence: ZFP57 NM_001109809.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0450
• Publications: 0 publications found

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]

ZFP57 Gene-Disease associations (from GenCC):

• diabetes mellitus, transient neonatal, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• transient neonatal diabetes mellitus

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040818453).
• BP6: Variant 6-29672993-G-C is Benign according to our data. Variant chr6-29672993-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130769.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000499 (76/152328) while in subpopulation SAS AF = 0.00726 (35/4824). AF 95% confidence interval is 0.00536. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109809.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFP57	NM_001109809.5	MANE Select	c.1118C>G	p.Ser373Cys	missense	Exon 5 of 5	NP_001103279.2
	ZFP57	NM_001366333.2		c.902C>G	p.Ser301Cys	missense	Exon 4 of 4	NP_001353262.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFP57	ENST00000376883.2	TSL:5 MANE Select	c.1118C>G	p.Ser373Cys	missense	Exon 5 of 5	ENSP00000366080.2
	ZFP57	ENST00000488757.6	TSL:1	c.902C>G	p.Ser301Cys	missense	Exon 4 of 4	ENSP00000418259.2

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00132 AC: 323 AN: 244660 AF XY: 0.00154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00207

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000696 AC: 1017 AN: 1460770 Hom.: 11 Cov.: 31 AF XY: 0.000826 AC XY: 600 AN XY: 726702

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00151 AC: 60 AN: 39700

South Asian (SAS) AF: 0.00712 AC: 614 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000114 AC: 127 AN: 1112010

Other (OTH) AF: 0.00331 AC: 200 AN: 60386

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74486

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5186

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00136 Hom.: 8

Bravo AF: 0.000374

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00148 AC: 173

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Diabetes mellitus, transient neonatal, 1 (2)
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.8
DANN	Benign	0.82
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.045
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.024
Sift	Benign	0.13	T
Sift4G	Benign	0.19	T
Polyphen		0.056	B
Vest4		0.13
MVP		0.33
MPC		0.44
ClinPred		0.015	T
GERP RS		2.1
Varity_R		0.042
gMVP		0.14
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs193232883; hg19: chr6-29640770;