NM_001321075.3:c.2074_2078delGTGGAinsT

Variant names:

• chr17-7190805-TCCAC-A
• rs2142803273
• NM_001321075.3:c.2074_2078delGTGGAinsT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001321075.3(DLG4):​c.2074_2078delGTGGAinsT​(p.Val692TrpfsTer12) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DLG4 NM_001321075.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 8.88
• Publications: 0 publications found

Genes affected

DLG4 (HGNC:2903): (discs large MAGUK scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DLG4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder 62

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 0.0464 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7190805-TCCAC-A is Pathogenic according to our data. Variant chr17-7190805-TCCAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 1329907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.2074_2078delGTGGAinsT	p.Val692TrpfsTer12	frameshift_variant, missense_variant	Exon 20 of 20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.2074_2078delGTGGAinsT	p.Val692TrpfsTer12	frameshift_variant, missense_variant	Exon 20 of 20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.9	c.2203_2207delGTGGAinsT	p.Val735TrpfsTer12	frameshift_variant, missense_variant	Exon 22 of 22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2173_2177delGTGGAinsT	p.Val725TrpfsTer12	frameshift_variant, missense_variant	Exon 20 of 20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1894_1898delGTGGAinsT	p.Val632TrpfsTer12	frameshift_variant, missense_variant	Exon 19 of 19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.*89_*93delGTGGAinsT		non_coding_transcript_exon_variant	Exon 21 of 21	2		ENSP00000467897.2
DLG4	ENST00000491753.2	n.*89_*93delGTGGAinsT		3_prime_UTR_variant	Exon 21 of 21	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder 62 Pathogenic:2 Other:1

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GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 01-07-2022 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Feb 28, 2023

Tumer Group, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Dec 21, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

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

Other links and lift over

dbSNP: rs2142803273; hg19: chr17-7094124;