dbSNP rs756267089: DLG4:p.Arg653Pro (chr17-7191911-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001321075.3(DLG4):c.1958G>C(p.Arg653Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R653H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

DLG4
NM_001321075.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.58

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a domain Guanylate kinase-like (size 175) in uniprot entity DLG4_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001321075.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41950458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3 link	c.1958G>C	p.Arg653Pro	missense_variant	Exon 18 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.1958G>C	p.Arg653Pro	missense_variant	Exon 18 of 20	2	NM_001321075.3	ENSP00000382425.2	P78352-1
DLG4	ENST00000648172.9 link	c.2087G>C	p.Arg696Pro	missense_variant	Exon 20 of 22			ENSP00000497806.3	P78352-2
DLG4	ENST00000648896.1 link	c.2057G>C	p.Arg686Pro	missense_variant	Exon 18 of 20			ENSP00000497546.1	A0A3B3ISQ5
DLG4	ENST00000649520.1 link	c.1778G>C	p.Arg593Pro	missense_variant	Exon 17 of 19			ENSP00000497647.1	B7Z647
DLG4	ENST00000491753.2 link	n.1996-553G>C		intron_variant	Intron 19 of 20	2		ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

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

Eigen

Benign

-0.16

Eigen_PC

Benign

0.072

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.016

MetaRNN

Benign

0.42

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

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.20

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

PhyloP100

4.6

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.1

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

REVEL

Benign

0.22

Sift

Uncertain

0.0040

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

Sift4G

Benign

0.21

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

Polyphen

0.071

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

Vest4

0.47, 0.47

MutPred

0.69

.;.;Loss of MoRF binding (P = 0.0796);.;.;.;.;.;

MVP

0.42

MPC

1.5

ClinPred

0.89

GERP RS

5.3

Varity_R

0.30

gMVP

0.81

Mutation Taster

=53/47

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over