chr17-7191344-C-T

Variant names:

• chr17-7191344-C-T
• rs1045675620
• NM_001365.5:c.2120G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001321075.3(DLG4):​c.1991G>A​(p.Arg664Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DLG4 NM_001321075.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2120G>A	p.Arg707Gln	missense	Exon 21 of 22	NP_001356.1	P78352-2
	DLG4	NM_001321075.3	MANE Select	c.1991G>A	p.Arg664Gln	missense	Exon 19 of 20	NP_001308004.1	P78352-1
	DLG4	NM_001321074.1		c.2111G>A	p.Arg704Gln	missense	Exon 21 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.2120G>A	p.Arg707Gln	missense	Exon 21 of 22	ENSP00000497806.3	P78352-2
	DLG4	ENST00000399506.9	TSL:2 MANE Select	c.1991G>A	p.Arg664Gln	missense	Exon 19 of 20	ENSP00000382425.2	P78352-1
	DLG4	ENST00000399510.8	TSL:1	c.2111G>A	p.Arg704Gln	missense	Exon 21 of 22	ENSP00000382428.3	B9EGL1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.27
Sift	Benign	0.072	T
Sift4G	Benign	0.16	T
Polyphen		0.68	P
Vest4		0.46
MutPred		0.51		Loss of MoRF binding (P = 0.0329)
MVP		0.64
MPC		2.3
ClinPred		0.98	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.82
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1045675620; hg19: chr17-7094663;