rs1135401779

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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 0.625 CDS is truncated, and there are 1 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 id is 431106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-87256691-TAGAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF292	NM_015021.3	c.3066_3069delAAGA	p.Glu1022AspfsTer3	frameshift_variant	Exon 8 of 8	ENST00000369577.8	NP_055836.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF292	ENST00000369577.8	c.3066_3069delAAGA	p.Glu1022AspfsTer3	frameshift_variant	Exon 8 of 8	1	NM_015021.3	ENSP00000358590.3

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

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder, autosomal dominant 64 Pathogenic:2

Feb 18, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Glu1022AspfsTer3 variant in ZNF292 was identified by our study in one individual with agenesis of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Glu1022AspfsTer3 variant in ZNF292 has been previously reported in 3 unrelated individuals with autosomal dominant intellectual developmental disorder 64 (ClinVar SCV000586726.1, PMID: 31723249). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in these 3 individuals with confirmed paternity and maternity (ClinVar SCV000586726.1, PMID: 31723249). This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 431106) and has been interpreted as pathogenic by OMIM and Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg and as likely pathogenic by University of Washington Center for Mendelian Genomics. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1022 and leads to a premature termination codon 3 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the ZNF292 gene is an established disease mechanism in autosomal dominant intellectual developmental disorder 64. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant intellectual developmental disorder 64. ACMG/AMP Criteria applied: PVS1_Strong, PS2, PS4_Supporting PM2_Supporting (Richards 2015). -

Neurodevelopmental disorder Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Intellectual disability Pathogenic:1

Aug 01, 2017

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo LOF variant identified in a male patient with developmental delay, constipation, feeding difficulties, hypothyreosis, short stature, facial dysmorphism. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1135401779; hg19: chr6-87966409;