NM_001366207.1:c.2665G>A

Variant names:

• chr3-197044640-C-T
• rs770242553
• NM_001366207.1:c.2665G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

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. 14/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14353824).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG1	NM_001366207.1	MANE Select	c.2665G>A	p.Ala889Thr	missense	Exon 25 of 25	NP_001353136.1	Q12959-4
	DLG1	NM_004087.2		c.2764G>A	p.Ala922Thr	missense	Exon 26 of 26	NP_004078.2	Q12959-2
	DLG1	NM_001366214.1		c.2761G>A	p.Ala921Thr	missense	Exon 26 of 26	NP_001353143.1	A0A590UJD9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG1	ENST00000667157.1	MANE Select	c.2665G>A	p.Ala889Thr	missense	Exon 25 of 25	ENSP00000499414.1	Q12959-4
	DLG1	ENST00000346964.6	TSL:1	c.2764G>A	p.Ala922Thr	missense	Exon 26 of 26	ENSP00000345731.2	Q12959-2
	DLG1	ENST00000419354.5	TSL:1	c.2698G>A	p.Ala900Thr	missense	Exon 26 of 26	ENSP00000407531.1	Q12959-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000205 AC: 5 AN: 244338 AF XY: 0.0000227

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000619 AC: 9 AN: 1452934 Hom.: 0 Cov.: 28 AF XY: 0.00000692 AC XY: 5 AN XY: 722916

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.0000230 AC: 1 AN: 43454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.0000708 AC: 6 AN: 84700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107396

Other (OTH) AF: 0.00 AC: 0 AN: 60004

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000565 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.98	L
PhyloP100		2.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.067
Sift	Benign	0.31	T
Sift4G	Benign	0.38	T
Polyphen		0.0090	B
Vest4		0.11
MutPred		0.65		Loss of glycosylation at P899 (P = 0.0792)
MVP		0.27
MPC		0.25
ClinPred		0.23	T
GERP RS		5.5
Varity_R		0.30
gMVP		0.42
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs770242553; hg19: chr3-196771511;