rs398122846

Positions:

• chrX-70451967-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000374360.8(DLG3):​c.1092dup​(p.Thr365HisfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DLG3 ENST00000374360.8 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.37

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 11 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-70451967-T-TC is Pathogenic according to our data. Variant chrX-70451967-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 29942.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG3	NM_021120.4	c.1092dup	p.Thr365HisfsTer13	frameshift_variant	7/19	ENST00000374360.8	NP_066943.2
DLG3	XM_006724625.3	c.1092dup	p.Thr365HisfsTer13	frameshift_variant	7/20		XP_006724688.1
DLG3	XM_006724626.3	c.1092dup	p.Thr365HisfsTer13	frameshift_variant	7/20		XP_006724689.1
DLG3	XM_011530883.2	c.1092dup	p.Thr365HisfsTer13	frameshift_variant	7/19		XP_011529185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG3	ENST00000374360.8	c.1092dup	p.Thr365HisfsTer13	frameshift_variant	7/19	1	NM_021120.4	ENSP00000363480
DLG3	ENST00000194900.8	c.1146dup	p.Thr383HisfsTer13	frameshift_variant	8/21	5		ENSP00000194900	P1
DLG3	ENST00000463252.5	n.1491dup		non_coding_transcript_exon_variant	6/19	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 90 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs398122846; hg19: chrX-69671817;