chr6-87256691-TAGAA-T

Variant names:

• chr6-87256691-TAGAA-T
• rs1135401779
• NM_015021.3:c.3066_3069delAAGA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015021.3(ZNF292):​c.3066_3069delAAGA​(p.Glu1022AspfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF292 NM_015021.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.46
• Publications: 2 publications found

Genes affected

ZNF292 (HGNC:18410): (zinc finger protein 292) This gene encodes a growth hormone-dependent, zinc finger transcription factor that functions as a tumor suppressor. Naturally occurring mutations in this gene are associated with gastric cancer, colorectal cancer, and chronic lymphocytic leukemia. [provided by RefSeq, May 2017]

ZNF292 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• intellectual developmental disorder, autosomal dominant 64

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 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. There are 68 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-87256691-TAGAA-T is Pathogenic according to our data. Variant chr6-87256691-TAGAA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 431106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015021.3. 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
	ZNF292	NM_015021.3	MANE Select	c.3066_3069delAAGA	p.Glu1022AspfsTer3	frameshift	Exon 8 of 8	NP_055836.1
	ZNF292	NM_001351444.2		c.2646_2649delAAGA	p.Glu882AspfsTer3	frameshift	Exon 9 of 9	NP_001338373.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF292	ENST00000369577.8	TSL:1 MANE Select	c.3066_3069delAAGA	p.Glu1022AspfsTer3	frameshift	Exon 8 of 8	ENSP00000358590.3
	ZNF292	ENST00000339907.8	TSL:5	c.3051_3054delAAGA	p.Glu1017AspfsTer3	frameshift	Exon 8 of 8	ENSP00000342847.4
	ZNF292	ENST00000699914.1		c.3066_3069delAAGA	p.Glu1022AspfsTer3	frameshift	Exon 11 of 11	ENSP00000514683.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual developmental disorder, autosomal dominant 64 (2)
1	-	-	Intellectual disability (1)
1	-	-	Neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1135401779; hg19: chr6-87966409;