rs11797456

Positions:

chrX-70445505-G-A

Variant summary

Our verdict is Benign. Variant got -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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.40

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Benign]. Clinvar id is 96020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70445505-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 95 XL gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00388

AC:

438

AN:

112803

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

AN XY:

34941

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

GnomAD3 exomes

AF:

0.00333

AC:

458

AN:

137498

Hom.:

AF XY:

0.00329

AC XY:

140

AN XY:

42606

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 SAS exome

AF:

0.00110

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

Gnomad4 AFR exome

AF:

0.000423

Gnomad4 AMR exome

AF:

0.000766

Gnomad4 ASJ exome

AF:

0.000949

Gnomad4 EAS exome

AF:

0.0000344

Gnomad4 SAS exome

AF:

0.000875

Gnomad4 FIN exome

AF:

0.00251

Gnomad4 NFE exome

AF:

0.00699

Gnomad4 OTH exome

AF:

0.00501

GnomAD4 genome

AF:

0.00388

AC:

438

AN:

112853

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

AN XY:

35001

show subpopulations

Gnomad4 AFR

AF:

0.000900

Gnomad4 AMR

AF:

0.00101

Gnomad4 ASJ

AF:

0.000376

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00271

Gnomad4 NFE

AF:

0.00692

Gnomad4 OTH

AF:

0.00258

Alfa

AF:

0.00563

Hom.:

226

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

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 13, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2019

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. -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over