chr17-7191976-C-T

Variant names:

• chr17-7191976-C-T
• rs375777526
• NM_001321075.3:c.1893G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001321075.3(DLG4):​c.1893G>A​(p.Ser631Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000637 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: DLG4 NM_001321075.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.50
• Publications: 1 publications found

Genes affected

DLG4 (HGNC:2903): (discs large MAGUK scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DLG4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder 62

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 17-7191976-C-T is Benign according to our data. Variant chr17-7191976-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 745399.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.1893G>A	p.Ser631Ser	synonymous_variant	Exon 18 of 20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.1893G>A	p.Ser631Ser	synonymous_variant	Exon 18 of 20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.9	c.2022G>A	p.Ser674Ser	synonymous_variant	Exon 20 of 22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.1992G>A	p.Ser664Ser	synonymous_variant	Exon 18 of 20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1713G>A	p.Ser571Ser	synonymous_variant	Exon 17 of 19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.1996-618G>A		intron_variant	Intron 19 of 20	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000174 AC: 25 AN: 143908 AF XY: 0.000191

Gnomad AFR exome AF: 0.000281

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000649 AC: 85 AN: 1308924 Hom.: 0 Cov.: 31 AF XY: 0.0000810 AC XY: 52 AN XY: 641716

African (AFR) AF: 0.0000725 AC: 2 AN: 27598

American (AMR) AF: 0.00 AC: 0 AN: 25062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18896

East Asian (EAS) AF: 0.00 AC: 0 AN: 33608

South Asian (SAS) AF: 0.00121 AC: 75 AN: 62112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48224

Middle Eastern (MID) AF: 0.000588 AC: 3 AN: 5102

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1035088

Other (OTH) AF: 0.0000939 AC: 5 AN: 53234

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74382

African (AFR) AF: 0.0000482 AC: 2 AN: 41484

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000580 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

DLG4-related disorder Benign:1

Jul 25, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

not provided Benign:1

May 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375777526; hg19: chr17-7095295; COSMIC: COSV57239337; COSMIC: COSV57239337;