X-70453793-G-A

Position:

• chrX-70453793-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021120.4(DLG3):​c.1302G>A​(p.Ser434Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DLG3 NM_021120.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.58

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]

DLG3-AS1 (HGNC:40182): (DLG3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG3	NM_021120.4	c.1302G>A	p.Ser434Ser	splice_region_variant, synonymous_variant	8/19	ENST00000374360.8	NP_066943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG3	ENST00000374360.8	c.1302G>A	p.Ser434Ser	splice_region_variant, synonymous_variant	8/19	1	NM_021120.4	ENSP00000363480.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 90 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked DLG3-related intellectual disability 90 (MIM#300850). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected males display a range of cognitive impairments with some showing additional clinical features such as seizures, abnormal behavior and/or facial dysmorphisms while female carriers have been reported to have variable symptoms due to skewed X-inactivation (PMIDs: 28777483; 32021600. (I) 0212 - Non-canonical splice variant without proven consequence on splicing (no functional evidence available). (SP) 0253 – This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are inconclusive. While loss of the WT donor site was not predicted, gain of an additional downstream donor site was predicted; however, it is unclear if the new donor site will affect splicing. Additionally, the affected nucleotide is highly conserved. (I) 0600 - Variant is located in the annotated PDZ domain (DECIPHER). (I) 0705 - No comparable variants non-canonical splice variants have previous evidence for pathogenicity. (I) 0804 - This variant has previously been described as a variant of uncertain significance in one case with consistent phenotype despite being absent in the general population. This variant has been identified in one individual with intellectual disability and developmental delay (GeneDx personal communication). (I) 0903 - This variant has limited evidence for segregation with disease. This variant has segregated in this individual's affected brother, but was absent in their two unaffected brothers and one unaffected sister (VCGS). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: Huang2022[CaseReport]) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: 19

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555961898; hg19: chrX-69673643;