NM_021120.4:c.358-300A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021120.4(DLG3):c.358-300A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 1,052,357 control chromosomes in the GnomAD database, including 81,333 homozygotes. There are 163,249 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 13737 hom., 17533 hem., cov: 21)

Exomes 𝑓: 0.47 ( 81333 hom. 163249 hem. )

Failed GnomAD Quality Control

Consequence

DLG3
NM_021120.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.1137406E-5).

BP6

Variant X-70448613-A-G is Benign according to our data. Variant chrX-70448613-A-G is described in ClinVar as Benign. ClinVar VariationId is 1277416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DLG3	NM_021120.4 link	c.358-300A>G	intron_variant	Intron 1 of 18	ENST00000374360.8	NP_066943.2	Q92796-1Q59FY1
DLG3	XM_006724625.3 link	c.358-300A>G	intron_variant	Intron 1 of 19		XP_006724688.1
DLG3	XM_011530883.2 link	c.358-300A>G	intron_variant	Intron 1 of 18		XP_011529185.1
DLG3	XM_006724626.3 link	c.358-300A>G	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>G		intron_variant	Intron 1 of 18	1	NM_021120.4	ENSP00000363480.3	Q92796-1
DLG3	ENST00000194900.8 link	c.391A>G	p.Thr131Ala	missense_variant	Exon 2 of 21	5		ENSP00000194900.4	Q5JUW8
DLG3	ENST00000463252.5 link	n.424-300A>G		intron_variant	Intron 1 of 18	5

Frequencies

GnomAD3 genomes

AF:

0.572

AC:

62234

AN:

108749

Hom.:

13723

Cov.:

show subpopulations

Gnomad AFR

AF:

0.794

Gnomad AMI

AF:

0.517

Gnomad AMR

AF:

0.607

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.325

Gnomad SAS

AF:

0.520

Gnomad FIN

AF:

0.550

Gnomad MID

AF:

0.480

Gnomad NFE

AF:

0.464

Gnomad OTH

AF:

0.591

GnomAD2 exomes

AF:

0.520

AC:

57081

AN:

109721

AF XY:

0.512

show subpopulations

Gnomad AFR exome

AF:

0.793

Gnomad AMR exome

AF:

0.612

Gnomad ASJ exome

AF:

0.510

Gnomad EAS exome

AF:

0.331

Gnomad FIN exome

AF:

0.550

Gnomad NFE exome

AF:

0.466

Gnomad OTH exome

AF:

0.515

GnomAD4 exome

AF:

0.474

AC:

498640

AN:

1052357

Hom.:

81333

Cov.:

AF XY:

0.475

AC XY:

163249

AN XY:

343961

show subpopulations

African (AFR)

AF:

0.794

AC:

19775

AN:

24899

American (AMR)

AF:

0.617

AC:

17215

AN:

27904

Ashkenazi Jewish (ASJ)

AF:

0.509

AC:

9488

AN:

18630

East Asian (EAS)

AF:

0.322

AC:

8725

AN:

27128

South Asian (SAS)

AF:

0.530

AC:

26411

AN:

49847

European-Finnish (FIN)

AF:

0.549

AC:

20226

AN:

36839

Middle Eastern (MID)

AF:

0.534

AC:

2181

AN:

4087

European-Non Finnish (NFE)

AF:

0.456

AC:

372909

AN:

818651

Other (OTH)

AF:

0.489

AC:

21710

AN:

44372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9111

18223

27334

36446

45557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12578

25156

37734

50312

62890

<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

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.573

AC:

62298

AN:

108803

Hom.:

13737

Cov.:

AF XY:

0.563

AC XY:

17533

AN XY:

31137

show subpopulations

African (AFR)

AF:

0.794

AC:

23608

AN:

29734

American (AMR)

AF:

0.607

AC:

6284

AN:

10353

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

1331

AN:

2599

East Asian (EAS)

AF:

0.325

AC:

1106

AN:

3406

South Asian (SAS)

AF:

0.520

AC:

1246

AN:

2395

European-Finnish (FIN)

AF:

0.550

AC:

3150

AN:

5730

Middle Eastern (MID)

AF:

0.459

AC:

AN:

209

European-Non Finnish (NFE)

AF:

0.464

AC:

24259

AN:

52243

Other (OTH)

AF:

0.595

AC:

876

AN:

1473

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

871

1742

2612

3483

4354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.484

Hom.:

14033

Bravo

AF:

0.592

TwinsUK

AF:

0.450

AC:

1668

ALSPAC

AF:

0.451

AC:

1302

ExAC

AF:

0.485

AC:

11439

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 18, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.95

BayesDel_noAF

Benign

-0.99

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.061

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.22

MetaRNN

Benign

0.000041

MetaSVM

Benign

-0.97

PhyloP100

0.98

PROVEAN

Benign

-1.3

REVEL

Benign

0.043

Sift

Benign

0.23

Sift4G

Benign

0.42

Vest4

0.017

ClinPred

0.014

GERP RS

2.5

Mutation Taster

=97/3

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over