Genetic Variant DLG1:p.Asp864His (chr3-197044715-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001366207.1(DLG1):c.2590G>C(p.Asp864His) variant causes a missense change. The variant allele was found at a frequency of 0.00000839 in 1,430,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D864N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

DLG1
NM_001366207.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.71

Publications

0 publications found

Variant links:

Genes affected

DLG1 (HGNC:2900): (discs large MAGUK scaffold protein 1) This gene encodes a multi-domain scaffolding protein that is required for normal development. This protein may have a role in septate junction formation, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. A multitude of transcript variants deriving from alternative splicing and the use of multiple alternate promoter have been observed, including some splice variants that may be specific to brain and other tissues. An upstream uORF may regulate translation at some splice variants of this gene. [provided by RefSeq, Sep 2018]

DLG1 Gene-Disease associations (from GenCC):

Brugada syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp

DLG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366207.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLG1	NM_001366207.1	MANE Select	c.2590G>C	p.Asp864His	missense	Exon 25 of 25	NP_001353136.1	Q12959-4
DLG1	NM_004087.2		c.2689G>C	p.Asp897His	missense	Exon 26 of 26	NP_004078.2	Q12959-2
DLG1	NM_001366214.1		c.2686G>C	p.Asp896His	missense	Exon 26 of 26	NP_001353143.1	A0A590UJD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLG1	ENST00000667157.1	MANE Select	c.2590G>C	p.Asp864His	missense	Exon 25 of 25	ENSP00000499414.1	Q12959-4
DLG1	ENST00000346964.6	TSL:1	c.2689G>C	p.Asp897His	missense	Exon 26 of 26	ENSP00000345731.2	Q12959-2
DLG1	ENST00000419354.5	TSL:1	c.2623G>C	p.Asp875His	missense	Exon 26 of 26	ENSP00000407531.1	Q12959-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000419

AC:

AN:

238900

AF XY:

0.00000772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000912

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000839

AC:

AN:

1430862

Hom.:

Cov.:

AF XY:

0.00000842

AC XY:

AN XY:

712194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32336

American (AMR)

AF:

0.00

AC:

AN:

41696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25458

East Asian (EAS)

AF:

0.00

AC:

AN:

38450

South Asian (SAS)

AF:

0.00

AC:

AN:

81864

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

1093940

Other (OTH)

AF:

0.00

AC:

AN:

58992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.1

PhyloP100

4.7

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.36

Sift

Benign

0.057

Sift4G

Benign

0.066

Polyphen

1.0

Vest4

0.73

MutPred

0.84

Gain of catalytic residue at L877 (P = 0.0524)

MVP

0.58

MPC

1.0

ClinPred

0.95

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.83

Mutation Taster

=29/71

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over