rs2142803273

Variant names:

• chr17-7190805-TCCAC-A
• rs2142803273
• NM_001365.5:c.2203_2207delGTGGAinsT

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

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 VariationId is 1329907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321075.3. 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
	DLG4	NM_001365.5	MANE Plus Clinical	c.2203_2207delGTGGAinsT	p.Val735TrpfsTer12	frameshift missense	Exon 22 of 22	NP_001356.1	P78352-2
	DLG4	NM_001321075.3	MANE Select	c.2074_2078delGTGGAinsT	p.Val692TrpfsTer12	frameshift missense	Exon 20 of 20	NP_001308004.1	P78352-1
	DLG4	NM_001321074.1		c.2194_2198delGTGGAinsT	p.Val732TrpfsTer12	frameshift missense	Exon 22 of 22	NP_001308003.1	B9EGL1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG4	ENST00000648172.9	MANE Plus Clinical	c.2203_2207delGTGGAinsT	p.Val735TrpfsTer12	frameshift missense	Exon 22 of 22	ENSP00000497806.3	P78352-2
	DLG4	ENST00000399506.9	TSL:2 MANE Select	c.2074_2078delGTGGAinsT	p.Val692TrpfsTer12	frameshift missense	Exon 20 of 20	ENSP00000382425.2	P78352-1
	DLG4	ENST00000399510.8	TSL:1	c.2194_2198delGTGGAinsT	p.Val732TrpfsTer12	frameshift missense	Exon 22 of 22	ENSP00000382428.3	B9EGL1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual developmental disorder 62 (3)

Computational scores

Source: dbNSFP v4.9

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;