Genetic Variant DLG1:p.Ala889Thr (chr3-197044640-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001366207.1(DLG1):c.2665G>A(p.Ala889Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,452,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

DLG1
NM_001366207.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14353824).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG1	NM_001366207.1 link	c.2665G>A	p.Ala889Thr	missense_variant	Exon 25 of 25	ENST00000667157.1	NP_001353136.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG1	ENST00000667157.1 link	c.2665G>A	p.Ala889Thr	missense_variant	Exon 25 of 25		NM_001366207.1	ENSP00000499414.1		Q12959-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

244338

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

132094

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 SAS exome

AF:

0.000104

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000619

AC:

AN:

1452934

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000708

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000565

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2764G>A (p.A922T) alteration is located in exon 26 (coding exon 25) of the DLG1 gene. This alteration results from a G to A substitution at nucleotide position 2764, causing the alanine (A) at amino acid position 922 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.30

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

Eigen

Benign

-0.14

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.0058

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.98

.;.;L;.;.;L;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.0

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

REVEL

Benign

0.067

Sift

Benign

0.31

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

Sift4G

Benign

0.38

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

Polyphen

0.0090

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

Vest4

0.11

MutPred

0.65

.;.;Loss of glycosylation at P899 (P = 0.0792);.;.;Loss of glycosylation at P899 (P = 0.0792);.;.;.;

MVP

0.27

MPC

0.25

ClinPred

0.23

GERP RS

5.5

Varity_R

0.30

gMVP

0.42

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