Genetic Variant DLG3:c.358-300A>T (chrX-70448613-A-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021120.4(DLG3):c.358-300A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,052,711 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes 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.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.000015 ( 0 hom. 8 hem. )

Consequence

DLG3
NM_021120.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.982

Publications

7 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052587956).

BS2

High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DLG3	NM_021120.4 link	c.358-300A>T	intron_variant	Intron 1 of 18	ENST00000374360.8	NP_066943.2	Q92796-1Q59FY1
DLG3	XM_006724625.3 link	c.358-300A>T	intron_variant	Intron 1 of 19		XP_006724688.1
DLG3	XM_011530883.2 link	c.358-300A>T	intron_variant	Intron 1 of 18		XP_011529185.1
DLG3	XM_006724626.3 link	c.358-300A>T	intron_variant	Intron 1 of 19		XP_006724689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLG3	ENST00000374360.8 link	c.358-300A>T		intron_variant	Intron 1 of 18	1	NM_021120.4	ENSP00000363480.3	Q92796-1
DLG3	ENST00000194900.8 link	c.391A>T	p.Thr131Ser	missense_variant	Exon 2 of 21	5		ENSP00000194900.4	Q5JUW8
DLG3	ENST00000463252.5 link	n.424-300A>T		intron_variant	Intron 1 of 18	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000456

AC:

AN:

109721

AF XY:

0.0000753

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

AF:

0.0000152

AC:

AN:

1052711

Hom.:

Cov.:

AF XY:

0.0000233

AC XY:

AN XY:

343979

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24904

American (AMR)

AF:

0.00

AC:

AN:

27908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18630

East Asian (EAS)

AF:

0.00

AC:

AN:

27132

South Asian (SAS)

AF:

0.000301

AC:

AN:

49857

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36843

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4087

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

818967

Other (OTH)

AF:

0.0000225

AC:

AN:

44383

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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.:

Alfa

AF:

0.00

Hom.:

14033

ExAC

AF:

0.000170

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.99

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.033

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.27

M_CAP

Benign

0.021

MetaRNN

Benign

0.053

MetaSVM

Benign

-1.0

PhyloP100

0.98

PROVEAN

Benign

-0.31

REVEL

Benign

0.031

Sift

Benign

0.63

Sift4G

Benign

0.77

Vest4

0.021

MutPred

0.46

Gain of disorder (P = 0.0304);

MVP

0.24

ClinPred

0.045

GERP RS

2.5

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over