rs606231123

Variant names:

• chr6-29673205-AGCCTGGGT-A
• rs606231123
• NM_001109809.5:c.898_905delACCCAGGC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_001109809.5(ZFP57):​c.898_905delACCCAGGC​(p.Thr300fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZFP57 NM_001109809.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.00200
• 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]

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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.443 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 6-29673205-AGCCTGGGT-A is Pathogenic according to our data. Variant chr6-29673205-AGCCTGGGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 721.Status of the report is no_assertion_criteria_provided, 0 stars.

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.898_905delACCCAGGC	p.Thr300fs	frameshift	Exon 5 of 5	NP_001103279.2	Q9NU63-3
	ZFP57	NM_001366333.2		c.682_689delACCCAGGC	p.Thr228fs	frameshift	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.898_905delACCCAGGC	p.Thr300fs	frameshift	Exon 5 of 5	ENSP00000366080.2	Q9NU63-3
	ZFP57	ENST00000488757.6	TSL:1	c.682_689delACCCAGGC	p.Thr228fs	frameshift	Exon 4 of 4	ENSP00000418259.2	A0A7I2S1M6
	ZFP57	ENST00000931172.1		c.898_905delACCCAGGC	p.Thr300fs	frameshift	Exon 4 of 4	ENSP00000601231.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244686 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460766 Hom.: 0 AF XY: 0.00000550 AC XY: 4 AN XY: 726702

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Diabetes mellitus, transient neonatal, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0020
Mutation Taster		=18/182	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs606231123; hg19: chr6-29640982;