3-197044683-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001366207.1(DLG1):c.2622A>G(p.Lys874=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,605,700 control chromosomes in the GnomAD database, including 2,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (165 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1874 hom.)
• Consequence: DLG1 NM_001366207.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.510

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 3-197044683-T-C is Benign according to our data. Variant chr3-197044683-T-C is described in ClinVar as [Benign]. Clinvar id is 3057052.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.51 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG1	NM_001366207.1	c.2622A>G	p.Lys874=	synonymous_variant	25/25	ENST00000667157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG1	ENST00000667157.1	c.2622A>G	p.Lys874=	synonymous_variant	25/25		NM_001366207.1

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5652 AN: 152192 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0510

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0421 AC: 10442 AN: 248234 Hom.: 287 AF XY: 0.0441 AC XY: 5927 AN XY: 134336

Gnomad AFR exome AF: 0.00719

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0492

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.0522

Gnomad FIN exome AF: 0.0739

Gnomad NFE exome AF: 0.0515

Gnomad OTH exome AF: 0.0401

GnomAD4 exome AF: 0.0468 AC: 68091 AN: 1453390 Hom.: 1874 Cov.: 29 AF XY: 0.0477 AC XY: 34515 AN XY: 723304

Gnomad4 AFR exome AF: 0.00707

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0480

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0543

Gnomad4 FIN exome AF: 0.0730

Gnomad4 NFE exome AF: 0.0492

Gnomad4 OTH exome AF: 0.0427

GnomAD4 genome AF: 0.0371 AC: 5654 AN: 152310 Hom.: 165 Cov.: 32 AF XY: 0.0377 AC XY: 2806 AN XY: 74486

Gnomad4 AFR AF: 0.00854

Gnomad4 AMR AF: 0.0324

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.0505

Gnomad4 FIN AF: 0.0774

Gnomad4 NFE AF: 0.0510

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0418 Hom.: 72

Bravo AF: 0.0308

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DLG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	5.3
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35370245; hg19: chr3-196771554;