X-70449482-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021120.4(DLG3):c.532G>T(p.Gly178Trp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 21)

Failed GnomAD Quality Control

Consequence

DLG3
NM_021120.4 missense, splice_region

Scores

Splicing: ADA: 0.5939

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG3	NM_021120.4 link	c.532G>T	p.Gly178Trp	missense_variant, splice_region_variant	Exon 3 of 19	ENST00000374360.8	NP_066943.2	Q92796-1Q59FY1
DLG3	XM_006724625.3 link	c.532G>T	p.Gly178Trp	missense_variant, splice_region_variant	Exon 3 of 20		XP_006724688.1
DLG3	XM_011530883.2 link	c.532G>T	p.Gly178Trp	missense_variant, splice_region_variant	Exon 3 of 19		XP_011529185.1
DLG3	XM_006724626.3 link	c.532G>T	p.Gly178Trp	missense_variant, splice_region_variant	Exon 3 of 20		XP_006724689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLG3	ENST00000374360.8 link	c.532G>T	p.Gly178Trp	missense_variant, splice_region_variant	Exon 3 of 19	1	NM_021120.4	ENSP00000363480.3	Q92796-1
DLG3	ENST00000194900.8 link	c.586G>T	p.Gly196Trp	missense_variant, splice_region_variant	Exon 4 of 21	5		ENSP00000194900.4	Q5JUW8
DLG3	ENST00000463252.5 link	n.598G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 19	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

110496

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

182861

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

110496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32712

African (AFR)

AF:

0.00

AC:

AN:

30273

American (AMR)

AF:

0.00

AC:

AN:

10417

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2622

East Asian (EAS)

AF:

0.00

AC:

AN:

3500

South Asian (SAS)

AF:

0.00

AC:

AN:

2538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52763

Other (OTH)

AF:

0.00

AC:

AN:

1491

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 90

Uncertain:1

Strand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The novel hemizygous DLG3 variant, p.Gly178Trp, alters a highly conserved residue. A maternally inherited nonsense variant, p.Arg217Ter, that lies close to the identified variant was found in a male with mental retardation along with another variant which has been predicted to be damaging in the PIN4 gene, p.Gly60Ser [PMID:23020937]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

.;N

PhyloP100

3.8

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

.;D

Vest4

0.61

MutPred

0.65

.;Loss of methylation at R176 (P = 0.0645);

MVP

0.68

MPC

1.8

ClinPred

0.76

GERP RS

4.2

Varity_R

0.76

gMVP

0.82

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.59

dbscSNV1_RF

Benign

0.66

SpliceAI score (max)

0.14

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over