3-197081057-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001366207.1(DLG1):c.1899T>G(p.Asp633Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,612,744 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D633G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0080 (6 hom., cov: 31)
  • Exomes 𝑓: 0.011 (132 hom.)
• Consequence: DLG1 NM_001366207.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.146

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070932508).
• BP6: Variant 3-197081057-A-C is Benign according to our data. Variant chr3-197081057-A-C is described in ClinVar as [Benign]. Clinvar id is 790388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 1217 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG1	NM_001366207.1	c.1899T>G	p.Asp633Glu	missense_variant	17/25	ENST00000667157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG1	ENST00000667157.1	c.1899T>G	p.Asp633Glu	missense_variant	17/25		NM_001366207.1

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 1217 AN: 152154 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00734 AC: 1840 AN: 250614 Hom.: 14 AF XY: 0.00741 AC XY: 1004 AN XY: 135474

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.00745

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000886

Gnomad FIN exome AF: 0.00439

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00802

GnomAD4 exome AF: 0.0115 AC: 16730 AN: 1460472 Hom.: 132 Cov.: 29 AF XY: 0.0110 AC XY: 8011 AN XY: 726560

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00807

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000767

Gnomad4 FIN exome AF: 0.00551

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.00799 AC: 1217 AN: 152272 Hom.: 6 Cov.: 31 AF XY: 0.00737 AC XY: 549 AN XY: 74462

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.0113 Hom.: 16

Bravo AF: 0.00863

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0134 AC: 115

ExAC AF: 0.00716 AC: 869

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0133

EpiControl AF: 0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	DLG1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.86	D;T;.;T;T;T;T;D;T
MetaRNN	Benign	0.0071	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.57	N;.;N;.;.;N;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.19	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T;T
Polyphen		0.0040	B;.;B;.;.;B;.;B;B
Vest4		0.16
MutPred		0.29		Gain of glycosylation at T664 (P = 0.0107);.;Gain of glycosylation at T664 (P = 0.0107);.;.;Gain of glycosylation at T664 (P = 0.0107);.;.;.;
MVP		0.71
MPC		0.24
ClinPred		0.0079	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.24

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

Other links and lift over

dbSNP: rs35430440; hg19: chr3-196807928; COSMIC: COSV100014961;