Genetic Variant DLG3:p.Gly43Glu (chrX-70445329-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_021120.4(DLG3):c.128G>A(p.Gly43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

DLG3
NM_021120.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.48

Publications

1 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:

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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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021120.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	NM_021120.4	MANE Select	c.128G>A	p.Gly43Glu	missense	Exon 1 of 19	NP_066943.2	Q92796-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLG3	ENST00000374360.8	TSL:1 MANE Select	c.128G>A	p.Gly43Glu	missense	Exon 1 of 19	ENSP00000363480.3	Q92796-1
DLG3	ENST00000194900.8	TSL:5	c.128G>A	p.Gly43Glu	missense	Exon 1 of 21	ENSP00000194900.4	Q5JUW8
DLG3	ENST00000949779.1		c.128G>A	p.Gly43Glu	missense	Exon 1 of 20	ENSP00000619838.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1054006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

343616

African (AFR)

AF:

0.00

AC:

AN:

25198

American (AMR)

AF:

0.00

AC:

AN:

28743

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18638

East Asian (EAS)

AF:

0.00

AC:

AN:

27577

South Asian (SAS)

AF:

0.00

AC:

AN:

50130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33565

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3967

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

821710

Other (OTH)

AF:

0.00

AC:

AN:

44478

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.034

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.032

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

2.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.38

REVEL

Benign

0.12

Sift

Uncertain

0.0020

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.37

MutPred

0.19

Loss of relative solvent accessibility (P = 0.1967)

MVP

0.36

MPC

1.0

ClinPred

0.43

GERP RS

1.8

PromoterAI

-0.048

Neutral

(source)

Varity_R

0.17

gMVP

0.62

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.47

Position offset: -4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over