X-70445188-C-CG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_021120.4(DLG3):c.-8dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000974 in 1,027,124 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.7e-7 (0 hom. 0 hem.)
• Consequence: DLG3 NM_021120.4 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.100

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70445188-C-CG is Pathogenic according to our data. Variant chrX-70445188-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 2576624.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.-8dup		5_prime_UTR_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3	c.-8dup		5_prime_UTR_variant	1/20
DLG3	XM_006724626.3	c.-8dup		5_prime_UTR_variant	1/20
DLG3	XM_011530883.2	c.-8dup		5_prime_UTR_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.-8dup		5_prime_UTR_variant	1/19	1	NM_021120.4
DLG3	ENST00000194900.8	c.-8dup		5_prime_UTR_variant	1/21	5		P1
DLG3	ENST00000463252.5	n.59dup		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.74e-7 AC: 1 AN: 1027124 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 326104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 90 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Neurogenetics Research Program, University of Adelaide

May 25, 2016

The variant segregates with disease and obligate carrier status in a large family with non-syndromic X-linked ID. Confirmed through 18 individuals over 6 generations. The variant lies within a region of significant linkage, maximum LOD= 2.40 at theta = 0 (in combination these data support that the variant is significantly depleted PS4). The variant causes a translation block confirmed independently by western blotting of patient cell lines and a luciferase reporter gene assay (PS3) The variant is absent from population databases (PM2). In combination, reduced protein expression is consistent with previous reports of disease-causing loss of function variants of DLG3. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69665038;