Variant 17-7191911-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_001321075.3(DLG4):c.1958G>A(p.Arg653His) variant causes a missense change. The variant allele was found at a frequency of 0.00000745 in 1,476,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DLG4
NM_001321075.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.58

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 links:

DLG4 (HGNC:):

DLG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DLG4. . Gene score misZ 4.933 (greater than the threshold 3.09). Trascript score misZ 4.8337 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, intellectual developmental disorder 62.

BP4

Computational evidence support a benign effect (MetaRNN=0.32011145).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG4	NM_001321075.3 linkuse as main transcript	c.1958G>A	p.Arg653His	missense_variant	18/20	ENST00000399506.9	NP_001308004.1	P78352-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DLG4	ENST00000399506.9 linkuse as main transcript	c.1958G>A	p.Arg653His	missense_variant	18/20	2	NM_001321075.3	ENSP00000382425.2	P78352-1
DLG4	ENST00000648172.8 linkuse as main transcript	c.2087G>A	p.Arg696His	missense_variant	20/22			ENSP00000497806.3	P78352-2
DLG4	ENST00000648896.1 linkuse as main transcript	c.2057G>A	p.Arg686His	missense_variant	18/20			ENSP00000497546.1	A0A3B3ISQ5
DLG4	ENST00000649520.1 linkuse as main transcript	c.1778G>A	p.Arg593His	missense_variant	17/19			ENSP00000497647.1	B7Z647
DLG4	ENST00000491753.2 linkuse as main transcript	n.1996-553G>A		intron_variant		2		ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1324884

Hom.:

Cov.:

AF XY:

0.00000768

AC XY:

AN XY:

650676

show subpopulations

Gnomad4 AFR exome

AF:

0.0000352

Gnomad4 AMR exome

AF:

0.0000356

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000304

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000576

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151534

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73992

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000213

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000831

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

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

Eigen

Benign

0.026

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.011

MetaRNN

Benign

0.32

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.7

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

REVEL

Benign

0.12

Sift

Uncertain

0.022

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

Sift4G

Benign

0.074

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

Polyphen

0.59

P;.;B;.;B;.;.;.

Vest4

0.20, 0.19

MutPred

0.69

.;.;Loss of MoRF binding (P = 0.1003);.;.;.;.;.;

MVP

0.39

MPC

1.4

ClinPred

0.36

GERP RS

5.3

Varity_R

0.067

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over