17-7196492-G-A

Variant names:

• chr17-7196492-G-A
• rs17203281
• NM_001365.5:c.1296C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001321075.3(DLG4):​c.1167C>T​(p.Ile389Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,613,368 control chromosomes in the GnomAD database, including 77,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6382 hom., cov: 32)
  • Exomes 𝑓: 0.31 (70993 hom.)
• Consequence: DLG4 NM_001321075.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.74
• Publications: 50 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-7196492-G-A is Benign according to our data. Variant chr17-7196492-G-A is described in ClinVar as Benign. ClinVar VariationId is 1255506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321075.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG4	NM_001365.5	MANE Plus Clinical	c.1296C>T	p.Ile432Ile	synonymous	Exon 12 of 22	NP_001356.1	P78352-2
	DLG4	NM_001321075.3	MANE Select	c.1167C>T	p.Ile389Ile	synonymous	Exon 10 of 20	NP_001308004.1	P78352-1
	DLG4	NM_001321074.1		c.1287C>T	p.Ile429Ile	synonymous	Exon 12 of 22	NP_001308003.1	B9EGL1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG4	ENST00000648172.9	MANE Plus Clinical	c.1296C>T	p.Ile432Ile	synonymous	Exon 12 of 22	ENSP00000497806.3	P78352-2
	DLG4	ENST00000399506.9	TSL:2 MANE Select	c.1167C>T	p.Ile389Ile	synonymous	Exon 10 of 20	ENSP00000382425.2	P78352-1
	DLG4	ENST00000399510.8	TSL:1	c.1287C>T	p.Ile429Ile	synonymous	Exon 12 of 22	ENSP00000382428.3	B9EGL1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42701 AN: 151992 Hom.: 6380 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.300

GnomAD2 exomes AF: 0.283 AC: 70531 AN: 249188 AF XY: 0.286

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.312

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.307 AC: 449018 AN: 1461258 Hom.: 70993 Cov.: 39 AF XY: 0.306 AC XY: 222099 AN XY: 726908

African (AFR) AF: 0.193 AC: 6470 AN: 33476

American (AMR) AF: 0.161 AC: 7213 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 8085 AN: 26130

East Asian (EAS) AF: 0.289 AC: 11479 AN: 39696

South Asian (SAS) AF: 0.201 AC: 17371 AN: 86250

European-Finnish (FIN) AF: 0.394 AC: 21056 AN: 53390

Middle Eastern (MID) AF: 0.309 AC: 1780 AN: 5766

European-Non Finnish (NFE) AF: 0.322 AC: 357400 AN: 1111460

Other (OTH) AF: 0.301 AC: 18164 AN: 60368

GnomAD4 genome AF: 0.281 AC: 42707 AN: 152110 Hom.: 6382 Cov.: 32 AF XY: 0.281 AC XY: 20898 AN XY: 74360

African (AFR) AF: 0.197 AC: 8181 AN: 41516

American (AMR) AF: 0.239 AC: 3654 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1060 AN: 3470

East Asian (EAS) AF: 0.310 AC: 1603 AN: 5166

South Asian (SAS) AF: 0.191 AC: 921 AN: 4822

European-Finnish (FIN) AF: 0.394 AC: 4166 AN: 10570

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22134 AN: 67968

Other (OTH) AF: 0.296 AC: 626 AN: 2112

Alfa AF: 0.304 Hom.: 27526

Bravo AF: 0.264

Asia WGS AF: 0.211 AC: 735 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	DLG4-related disorder (1)
-	-	1	Intellectual developmental disorder 62 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.3
DANN	Benign	0.80
PhyloP100		-2.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs17203281; hg19: chr17-7099811; COSMIC: COSV57236265; COSMIC: COSV57236265;