Variant X-70454271-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_021120.4(DLG3):c.1360C>T(p.Arg454Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,209,698 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

DLG3
NM_021120.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.375

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:

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

DLG3-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2660221).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG3	NM_021120.4 link	c.1360C>T	p.Arg454Trp	missense_variant	9/19	ENST00000374360.8	NP_066943.2	Q92796-1Q59FY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG3	ENST00000374360.8 link	c.1360C>T	p.Arg454Trp	missense_variant	9/19	1	NM_021120.4	ENSP00000363480.3		Q92796-1

Frequencies

GnomAD3 genomes

AF:

0.0000358

AC:

AN:

111844

Hom.:

Cov.:

AF XY:

0.0000588

AC XY:

AN XY:

34040

show subpopulations

Gnomad AFR

AF:

0.0000976

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

182629

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67087

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097854

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000358

AC:

AN:

111844

Hom.:

Cov.:

AF XY:

0.0000588

AC XY:

AN XY:

34040

show subpopulations

Gnomad4 AFR

AF:

0.0000976

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.1360C>T (p.R454W) alteration is located in exon 9 (coding exon 9) of the DLG3 gene. This alteration results from a C to T substitution at nucleotide position 1360, causing the arginine (R) at amino acid position 454 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;T;.

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Pathogenic

2.9

.;M;.

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.6

D;D;N

REVEL

Benign

0.27

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.35

MutPred

0.56

.;Gain of catalytic residue at L452 (P = 0.0075);.;

MVP

0.48

MPC

1.8

ClinPred

0.95

GERP RS

4.0

Varity_R

0.49

gMVP

0.71

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