Genetic Variant DLG5:p.Pro1481Gln (chr10-77811115-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004747.4(DLG5):c.4442C>A(p.Pro1481Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0434 in 1,610,818 control chromosomes in the GnomAD database, including 2,215 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.044 ( 232 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1983 hom. )

Consequence

DLG5
NM_004747.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.98

Variant links:

Genes affected

DLG5 (HGNC:2904): (discs large MAGUK scaffold protein 5) This gene encodes a member of the family of discs large (DLG) homologs, a subset of the membrane-associated guanylate kinase (MAGUK) superfamily. The MAGUK proteins are composed of a catalytically inactive guanylate kinase domain, in addition to PDZ and SH3 domains, and are thought to function as scaffolding molecules at sites of cell-cell contact. The protein encoded by this gene localizes to the plasma membrane and cytoplasm, and interacts with components of adherens junctions and the cytoskeleton. It is proposed to function in the transmission of extracellular signals to the cytoskeleton and in the maintenance of epithelial cell structure. Alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

DLG5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017066598).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG5	NM_004747.4 link	c.4442C>A	p.Pro1481Gln	missense_variant	Exon 23 of 32	ENST00000372391.7	NP_004738.3	Q8TDM6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG5	ENST00000372391.7 link	c.4442C>A	p.Pro1481Gln	missense_variant	Exon 23 of 32	1	NM_004747.4	ENSP00000361467.2		Q8TDM6-1

Frequencies

GnomAD3 genomes

AF:

0.0444

AC:

6743

AN:

151826

Hom.:

231

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0316

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.0472

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.0638

Gnomad FIN

AF:

0.0414

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0362

Gnomad OTH

AF:

0.0451

GnomAD3 exomes

AF:

0.0573

AC:

14266

AN:

248976

Hom.:

633

AF XY:

0.0574

AC XY:

7737

AN XY:

134798

show subpopulations

Gnomad AFR exome

AF:

0.0350

Gnomad AMR exome

AF:

0.0438

Gnomad ASJ exome

AF:

0.130

Gnomad EAS exome

AF:

0.179

Gnomad SAS exome

AF:

0.0531

Gnomad FIN exome

AF:

0.0451

Gnomad NFE exome

AF:

0.0415

Gnomad OTH exome

AF:

0.0612

GnomAD4 exome

AF:

0.0433

AC:

63113

AN:

1458876

Hom.:

1983

Cov.:

AF XY:

0.0441

AC XY:

32015

AN XY:

725752

show subpopulations

Gnomad4 AFR exome

AF:

0.0339

Gnomad4 AMR exome

AF:

0.0462

Gnomad4 ASJ exome

AF:

0.133

Gnomad4 EAS exome

AF:

0.176

Gnomad4 SAS exome

AF:

0.0516

Gnomad4 FIN exome

AF:

0.0446

Gnomad4 NFE exome

AF:

0.0349

Gnomad4 OTH exome

AF:

0.0576

GnomAD4 genome

AF:

0.0444

AC:

6753

AN:

151942

Hom.:

232

Cov.:

AF XY:

0.0448

AC XY:

3326

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0316

Gnomad4 AMR

AF:

0.0476

Gnomad4 ASJ

AF:

0.140

Gnomad4 EAS

AF:

0.177

Gnomad4 SAS

AF:

0.0632

Gnomad4 FIN

AF:

0.0414

Gnomad4 NFE

AF:

0.0362

Gnomad4 OTH

AF:

0.0475

Alfa

AF:

0.0463

Hom.:

500

Bravo

AF:

0.0471

TwinsUK

AF:

0.0375

AC:

139

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.0304

AC:

134

ESP6500EA

AF:

0.0422

AC:

363

ExAC

AF:

0.0573

AC:

6953

EpiCase

AF:

0.0411

EpiControl

AF:

0.0392

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.20

.;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.86

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.0

.;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.083

Sift

Benign

0.10

T;T

Sift4G

Uncertain

0.053

T;T

Polyphen

0.0

.;B

Vest4

0.066

MPC

0.22

ClinPred

0.011

GERP RS

0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.030

gMVP

0.29

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over