X-70445359-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_021120.4(DLG3):c.159del(p.Tyr54ThrfsTer67) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: DLG3 NM_021120.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.05

Genes affected

DLG3 (HGNC:2902): (discs large MAGUK scaffold protein 3) This gene encodes a member of the membrane-associated guanylate kinase protein family. The encoded protein may play a role in clustering of NMDA receptors at excitatory synapses. It may also negatively regulate cell proliferation through interaction with the C-terminal region of the adenomatosis polyposis coli tumor suppressor protein. Mutations in this gene have been associated with X-linked cognitive disability. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70445359-GC-G is Pathogenic according to our data. Variant chrX-70445359-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.159del	p.Tyr54ThrfsTer67	frameshift_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3	c.159del	p.Tyr54ThrfsTer67	frameshift_variant	1/20
DLG3	XM_011530883.2	c.159del	p.Tyr54ThrfsTer67	frameshift_variant	1/19
DLG3	XM_006724626.3	c.159del	p.Tyr54ThrfsTer67	frameshift_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.159del	p.Tyr54ThrfsTer67	frameshift_variant	1/19	1	NM_021120.4
DLG3	ENST00000194900.8	c.159del	p.Tyr54ThrfsTer73	frameshift_variant	1/21	5		P1
DLG3	ENST00000463252.5	n.225del		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 90 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Dec 16, 2022

PVS1, PM2 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 12, 2018

The c.159delC variant in the DLG3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.159delC variant causes a frameshift starting with codon Tyrosine 54, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 67 of the new reading frame, denoted p.Tyr54ThrfsX67. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.159delC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.159delC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1602857000; hg19: chrX-69665209;