3-197069219-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001366207.1(DLG1):c.2047C>T(p.Arg683Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,584,806 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: DLG1 NM_001366207.1 missense, splice_region
• Scores: Splicing: ADA: 0.9834
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.14

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010337979).
• BP6: Variant 3-197069219-G-A is Benign according to our data. Variant chr3-197069219-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3045357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG1	NM_001366207.1	c.2047C>T	p.Arg683Cys	missense_variant, splice_region_variant	19/25	ENST00000667157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG1	ENST00000667157.1	c.2047C>T	p.Arg683Cys	missense_variant, splice_region_variant	19/25		NM_001366207.1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 174 AN: 151782 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00286

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00102

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00106 AC: 247 AN: 233648 Hom.: 1 AF XY: 0.00110 AC XY: 139 AN XY: 126932

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000195

Gnomad ASJ exome AF: 0.00307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000360

Gnomad FIN exome AF: 0.00197

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00102 AC: 1462 AN: 1433024 Hom.: 3 Cov.: 27 AF XY: 0.00103 AC XY: 731 AN XY: 712852

Gnomad4 AFR exome AF: 0.0000934

Gnomad4 AMR exome AF: 0.000192

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000367

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000917

GnomAD4 genome AF: 0.00115 AC: 174 AN: 151782 Hom.: 3 Cov.: 32 AF XY: 0.00127 AC XY: 94 AN XY: 74092

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00286

Gnomad4 NFE AF: 0.00102

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00112

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000955 AC: 116

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DLG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2022

This variant is classified as likely 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	D;.;D;D;D;D;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D;.;D;D;D;D;D;D
Sift4G	Uncertain	0.045	D;D;D;D;D;D;D;D
Polyphen		0.0030	B;.;B;.;.;B;B;.
Vest4		0.66
MVP		0.54
MPC		0.63
ClinPred		0.097	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.11		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: rs74674649; hg19: chr3-196796090;