3-197065292-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001366207.1(DLG1):c.2357G>A(p.Arg786Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,606,026 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 31)
  • Exomes 𝑓: 0.021 (382 hom.)
• Consequence: DLG1 NM_001366207.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.04

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067587793).
• BP6: Variant 3-197065292-C-T is Benign according to our data. Variant chr3-197065292-C-T is described in ClinVar as [Benign]. Clinvar id is 3041899.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0147 (2235/151924) while in subpopulation NFE AF= 0.0238 (1616/67966). AF 95% confidence interval is 0.0228. There are 20 homozygotes in gnomad4. There are 1106 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 2235 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG1	NM_001366207.1	c.2357G>A	p.Arg786Gln	missense_variant	22/25	ENST00000667157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG1	ENST00000667157.1	c.2357G>A	p.Arg786Gln	missense_variant	22/25		NM_001366207.1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2235 AN: 151806 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00526

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.00912

GnomAD3 exomes AF: 0.0165 AC: 4032 AN: 244010 Hom.: 46 AF XY: 0.0168 AC XY: 2215 AN XY: 131934

Gnomad AFR exome AF: 0.00341

Gnomad AMR exome AF: 0.00527

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.00727

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0251

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0207 AC: 30160 AN: 1454102 Hom.: 382 Cov.: 31 AF XY: 0.0205 AC XY: 14830 AN XY: 723296

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.00571

Gnomad4 ASJ exome AF: 0.00570

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00755

Gnomad4 FIN exome AF: 0.0290

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0147 AC: 2235 AN: 151924 Hom.: 20 Cov.: 31 AF XY: 0.0149 AC XY: 1106 AN XY: 74210

Gnomad4 AFR AF: 0.00388

Gnomad4 AMR AF: 0.00525

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00749

Gnomad4 FIN AF: 0.0291

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.00902

Alfa AF: 0.0211 Hom.: 59

Bravo AF: 0.0124

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0245 AC: 211

ExAC AF: 0.0170 AC: 2061

Asia WGS AF: 0.00260 AC: 9 AN: 3476

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

Aug 08, 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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D;D;D;D
MetaRNN	Benign	0.0068	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D;D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.10	T;.;T;T;T;T;T;D;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;.;P;.;.;P;.;P;.
Vest4		0.57
MPC		0.74
ClinPred		0.039	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.87

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: rs78190191; hg19: chr3-196792163; COSMIC: COSV99040415; COSMIC: COSV99040415;