Genetic Variant NM_021120.4:c.149G>T (chrX-70445350-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_021120.4(DLG3):c.149G>T(p.Gly50Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000945 in 1,058,304 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. G50A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

DLG3
NM_021120.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.45

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3259149).

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.149G>T	p.Gly50Val	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.149G>T	p.Gly50Val	missense	Exon 1 of 19	ENSP00000363480.3	Q92796-1
DLG3	ENST00000194900.8	TSL:5	c.149G>T	p.Gly50Val	missense	Exon 1 of 21	ENSP00000194900.4	Q5JUW8
DLG3	ENST00000949779.1		c.149G>T	p.Gly50Val	missense	Exon 1 of 20	ENSP00000619838.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.45e-7

AC:

AN:

1058304

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

344800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25303

American (AMR)

AF:

0.00

AC:

AN:

29397

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18681

East Asian (EAS)

AF:

0.00

AC:

AN:

27746

South Asian (SAS)

AF:

0.00

AC:

AN:

50305

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34677

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4022

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

823559

Other (OTH)

AF:

0.00

AC:

AN:

44614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.047

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

5.5

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.010

REVEL

Benign

0.20

Sift

Uncertain

0.028

Sift4G

Uncertain

0.037

Polyphen

0.75

Vest4

0.38

MutPred

0.52

Gain of sheet (P = 0.0028)

MVP

0.47

MPC

1.5

ClinPred

0.84

GERP RS

3.7

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.24

gMVP

0.40

Mutation Taster

=95/5

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over