X-70449787-C-T

Variant names:

• chrX-70449787-C-T
• rs1213060424
• NM_021120.4:c.631C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_021120.4(DLG3):​c.631C>T​(p.Arg211*) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R211R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DLG3 NM_021120.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 1.60
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 90

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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-70449787-C-T is Pathogenic according to our data. Variant chrX-70449787-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 521892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG3	NM_021120.4	c.631C>T	p.Arg211*	stop_gained	Exon 4 of 19	ENST00000374360.8	NP_066943.2
DLG3	XM_006724625.3	c.631C>T	p.Arg211*	stop_gained	Exon 4 of 20		XP_006724688.1
DLG3	XM_011530883.2	c.631C>T	p.Arg211*	stop_gained	Exon 4 of 19		XP_011529185.1
DLG3	XM_006724626.3	c.631C>T	p.Arg211*	stop_gained	Exon 4 of 20		XP_006724689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG3	ENST00000374360.8	c.631C>T	p.Arg211*	stop_gained	Exon 4 of 19	1	NM_021120.4	ENSP00000363480.3
DLG3	ENST00000194900.8	c.685C>T	p.Arg229*	stop_gained	Exon 5 of 21	5		ENSP00000194900.4
DLG3	ENST00000463252.5	n.697C>T		non_coding_transcript_exon_variant	Exon 4 of 19	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jun 15, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Sep 30, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge

DLG3-related disorder Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 02-11-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.
LIST_S2	Benign	0.0	.;.
MetaRNN	Benign	0.0	.;.
MutationAssessor	Benign	0.0	.;.
PhyloP100		1.6
PROVEAN	Benign	0.0	.;.
Sift	Pathogenic	0.0	.;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.76
GERP RS		4.5
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1213060424; hg19: chrX-69669637; COSMIC: COSV107210825; COSMIC: COSV107210825;