rs114591600

Variant names:

• chr6-29673737-C-T
• rs114591600
• NM_001109809.5:c.374G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-29673737-C-T
• chr6-29673737-C-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.374G>A​(p.Arg125Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,016 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.014 (21 hom., cov: 32)
  • Exomes 𝑓: 0.017 (298 hom.)
• Consequence: ZFP57 NM_001109809.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -2.39
• Publications: 6 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]

MOG (HGNC:7197): (myelin oligodendrocyte glycoprotein) The product of this gene is a membrane protein expressed on the oligodendrocyte cell surface and the outermost surface of myelin sheaths. Due to this localization, it is a primary target antigen involved in immune-mediated demyelination. This protein may be involved in completion and maintenance of the myelin sheath and in cell-cell communication. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MOG Gene-Disease associations (from GenCC):

• narcolepsy 7

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.002755016).
• BP6: Variant 6-29673737-C-T is Benign according to our data. Variant chr6-29673737-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130774.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0137 (2091/152320) while in subpopulation SAS AF = 0.0282 (136/4826). AF 95% confidence interval is 0.0243. There are 21 homozygotes in GnomAd4. There are 1073 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFP57	NM_001109809.5	MANE Select	c.374G>A	p.Arg125Gln	missense	Exon 5 of 5	NP_001103279.2	Q9NU63-3
	ZFP57	NM_001366333.2		c.158G>A	p.Arg53Gln	missense	Exon 4 of 4	NP_001353262.1	A0A7I2S1M6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFP57	ENST00000376883.2	TSL:5 MANE Select	c.374G>A	p.Arg125Gln	missense	Exon 5 of 5	ENSP00000366080.2	Q9NU63-3
	ZFP57	ENST00000488757.6	TSL:1	c.158G>A	p.Arg53Gln	missense	Exon 4 of 4	ENSP00000418259.2	A0A7I2S1M6
	ZFP57	ENST00000931172.1		c.374G>A	p.Arg125Gln	missense	Exon 4 of 4	ENSP00000601231.1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2090 AN: 152202 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00576

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0165 AC: 3988 AN: 241450 AF XY: 0.0177

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00565

Gnomad EAS exome AF: 0.00235

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0167 AC: 24376 AN: 1460696 Hom.: 298 Cov.: 32 AF XY: 0.0173 AC XY: 12567 AN XY: 726676

African (AFR) AF: 0.00445 AC: 149 AN: 33480

American (AMR) AF: 0.00420 AC: 188 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00566 AC: 148 AN: 26136

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39700

South Asian (SAS) AF: 0.0349 AC: 3007 AN: 86258

European-Finnish (FIN) AF: 0.0384 AC: 2005 AN: 52252

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.0162 AC: 18007 AN: 1111992

Other (OTH) AF: 0.0135 AC: 814 AN: 60386

GnomAD4 genome AF: 0.0137 AC: 2091 AN: 152320 Hom.: 21 Cov.: 32 AF XY: 0.0144 AC XY: 1073 AN XY: 74486

African (AFR) AF: 0.00601 AC: 250 AN: 41570

American (AMR) AF: 0.00634 AC: 97 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00578 AC: 30 AN: 5194

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4826

European-Finnish (FIN) AF: 0.0334 AC: 354 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0172 AC: 1172 AN: 68028

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.0141 Hom.: 61

Bravo AF: 0.0102

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.0106 AC: 26

ESP6500EA AF: 0.0141 AC: 71

ExAC AF: 0.0175 AC: 2030

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0140

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.024
DANN	Benign	0.69
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.90	T
PhyloP100		-2.4
PrimateAI	Benign	0.15	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.0040
Sift	Benign	0.71	T
Sift4G	Benign	0.86	T
Polyphen		0.0020	B
Vest4		0.021
MPC		0.48
ClinPred		0.00040	T
GERP RS		-4.2
gMVP		0.093
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114591600; hg19: chr6-29641514; COSMIC: COSV65305836; COSMIC: COSV65305836;