X-70445243-T-G

Position:

• chrX-70445243-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_021120.4(DLG3):​c.42T>G​(p.Tyr14*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: DLG3 NM_021120.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.201

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.983 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70445243-T-G is Pathogenic according to our data. Variant chrX-70445243-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 988400.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG3	NM_021120.4	c.42T>G	p.Tyr14*	stop_gained	1/19	ENST00000374360.8	NP_066943.2
DLG3	XM_006724625.3	c.42T>G	p.Tyr14*	stop_gained	1/20		XP_006724688.1
DLG3	XM_011530883.2	c.42T>G	p.Tyr14*	stop_gained	1/19		XP_011529185.1
DLG3	XM_006724626.3	c.42T>G	p.Tyr14*	stop_gained	1/20		XP_006724689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG3	ENST00000374360.8	c.42T>G	p.Tyr14*	stop_gained	1/19	1	NM_021120.4	ENSP00000363480.3
DLG3	ENST00000194900.8	c.42T>G	p.Tyr14*	stop_gained	1/21	5		ENSP00000194900.4
DLG3	ENST00000463252.5	n.108T>G		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Jun 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.70	D
Vest4		0.61
GERP RS		-1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2086553104; hg19: chrX-69665093;