rs11797456

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_021120.4(DLG3):c.304G>A(p.Gly102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,191,109 control chromosomes in the GnomAD database, including 14 homozygotes. There are 2,067 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 0 hom., 95 hem., cov: 24)

Exomes 𝑓: 0.0058 ( 14 hom. 1972 hem. )

Consequence

DLG3
NM_021120.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.40

Publications

5 publications found

Variant links:

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

DLG3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004940212).

BP6

Variant X-70445505-G-A is Benign according to our data. Variant chrX-70445505-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 95 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG3	NM_021120.4 link	c.304G>A	p.Gly102Ser	missense_variant	Exon 1 of 19	ENST00000374360.8	NP_066943.2	Q92796-1Q59FY1
DLG3	XM_006724625.3 link	c.304G>A	p.Gly102Ser	missense_variant	Exon 1 of 20		XP_006724688.1
DLG3	XM_011530883.2 link	c.304G>A	p.Gly102Ser	missense_variant	Exon 1 of 19		XP_011529185.1
DLG3	XM_006724626.3 link	c.304G>A	p.Gly102Ser	missense_variant	Exon 1 of 20		XP_006724689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLG3	ENST00000374360.8 link	c.304G>A	p.Gly102Ser	missense_variant	Exon 1 of 19	1	NM_021120.4	ENSP00000363480.3	Q92796-1
DLG3	ENST00000194900.8 link	c.304G>A	p.Gly102Ser	missense_variant	Exon 1 of 21	5		ENSP00000194900.4	Q5JUW8
DLG3	ENST00000463252.5 link	n.370G>A		non_coding_transcript_exon_variant	Exon 1 of 19	5

Frequencies

GnomAD3 genomes

AF:

0.00388

AC:

438

AN:

112803

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000902

Gnomad AMI

AF:

0.0117

Gnomad AMR

AF:

0.00102

Gnomad ASJ

AF:

0.000376

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00271

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.00691

Gnomad OTH

AF:

0.00261

GnomAD2 exomes

AF:

0.00333

AC:

458

AN:

137498

AF XY:

0.00329

show subpopulations

Gnomad AFR exome

AF:

0.000832

Gnomad AMR exome

AF:

0.000756

Gnomad ASJ exome

AF:

0.000760

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00179

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00331

GnomAD4 exome

AF:

0.00579

AC:

6245

AN:

1078256

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

1972

AN XY:

350430

show subpopulations

African (AFR)

AF:

0.000423

AC:

AN:

25994

American (AMR)

AF:

0.000766

AC:

AN:

32657

Ashkenazi Jewish (ASJ)

AF:

0.000949

AC:

AN:

18971

East Asian (EAS)

AF:

0.0000344

AC:

AN:

29078

South Asian (SAS)

AF:

0.000875

AC:

AN:

51419

European-Finnish (FIN)

AF:

0.00251

AC:

AN:

38182

Middle Eastern (MID)

AF:

0.000974

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.00699

AC:

5818

AN:

832506

Other (OTH)

AF:

0.00501

AC:

227

AN:

45343

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

278

555

833

1110

1388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00388

AC:

438

AN:

112853

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

AN XY:

35001

show subpopulations

African (AFR)

AF:

0.000900

AC:

AN:

31125

American (AMR)

AF:

0.00101

AC:

AN:

10848

Ashkenazi Jewish (ASJ)

AF:

0.000376

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3520

South Asian (SAS)

AF:

0.00

AC:

AN:

2756

European-Finnish (FIN)

AF:

0.00271

AC:

AN:

6279

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00692

AC:

368

AN:

53216

Other (OTH)

AF:

0.00258

AC:

AN:

1551

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00523

Hom.:

227

Bravo

AF:

0.00328

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.000806

AC:

ESP6500EA

AF:

0.00443

AC:

ExAC

AF:

0.00295

AC:

346

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 28, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 20, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, X-linked 90

Benign:1

Jan 31, 2025

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Literature review. This variant is a missense which replaces a glycine with a serine at position 102. Hemizygous pathogenic variants in DLG3 are reported in an autosomal dominant intellectual disability (OMIM #300850). This variant is present in 2067 males individuals in the population database gnomAD (v4.1.0). It has previously been reported as benign in ClinVar and in the literature (PMID:25649377). In silico prediction scores are in favor of an absence of effect. Based on these evidences, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.039

T;T

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.20

.;N

PhyloP100

3.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.28

N;N

REVEL

Benign

0.064

Sift

Benign

0.21

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0010

.;B

Vest4

0.043

MVP

0.38

MPC

0.86

ClinPred

0.0056

GERP RS

3.8

Varity_R

0.094

gMVP

0.48

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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rs11797456

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over