chr17-7190731-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001321075.3(DLG4):c.2152G>A(p.Val718Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,613,744 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 7 hom. )

Consequence

DLG4
NM_001321075.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.45

Publications

6 publications found

Variant links:

Genes affected

DLG4 (HGNC:2903): (discs large MAGUK scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DLG4 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual developmental disorder 62
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

DLG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01369518).

BP6

Variant 17-7190731-C-T is Benign according to our data. Variant chr17-7190731-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 774928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 262 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3 link	c.2152G>A	p.Val718Ile	missense_variant	Exon 20 of 20	ENST00000399506.9	NP_001308004.1	P78352-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLG4	ENST00000399506.9 link	c.2152G>A	p.Val718Ile	missense_variant	Exon 20 of 20	2	NM_001321075.3	ENSP00000382425.2	P78352-1
DLG4	ENST00000648172.9 link	c.2281G>A	p.Val761Ile	missense_variant	Exon 22 of 22			ENSP00000497806.3	P78352-2
DLG4	ENST00000648896.1 link	c.2251G>A	p.Val751Ile	missense_variant	Exon 20 of 20			ENSP00000497546.1	A0A3B3ISQ5
DLG4	ENST00000649520.1 link	c.1972G>A	p.Val658Ile	missense_variant	Exon 19 of 19			ENSP00000497647.1	B7Z647
DLG4	ENST00000491753.2 link	n.*167G>A		non_coding_transcript_exon_variant	Exon 21 of 21	2		ENSP00000467897.2	B7Z3U2
DLG4	ENST00000491753.2 link	n.*167G>A		3_prime_UTR_variant	Exon 21 of 21	2		ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

262

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00247

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.00177

AC:

442

AN:

249144

AF XY:

0.00182

show subpopulations

Gnomad AFR exome

AF:

0.000839

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.00298

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00242

AC:

3543

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

1701

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33472

American (AMR)

AF:

0.00195

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00293

AC:

3256

AN:

1111722

Other (OTH)

AF:

0.00212

AC:

128

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

162

324

485

647

809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152240

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41534

American (AMR)

AF:

0.00418

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00247

AC:

168

AN:

68002

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00247

Hom.:

Bravo

AF:

0.00196

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00203

AC:

ExAC

AF:

0.00174

AC:

211

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00379

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DLG4: BP4, BS1 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

DLG4-related disorder

Benign:1

Aug 24, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.42

.;.;T;T;T;.;T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.093

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.90

D;D;D;.;D;D;D;D

M_CAP

Benign

0.0038

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.56

.;.;N;.;.;.;.;.

PhyloP100

1.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.35

.;N;N;.;.;.;.;.

REVEL

Benign

0.048

Sift

Benign

0.26

.;T;T;.;.;.;.;.

Sift4G

Benign

0.36

.;T;T;.;.;.;.;.

Polyphen

0.0010

B;.;B;.;B;.;.;.

Vest4

0.13, 0.13

MVP

0.48

MPC

1.1

ClinPred

0.012

GERP RS

4.1

Varity_R

0.086

gMVP

0.18

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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chr17-7190731-C-T

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