NM_001365.5:c.2036G>T

Variant names:

• chr17-7191962-C-A
• rs1488126978
• NM_001365.5:c.2036G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365.5(DLG4):​c.2036G>T​(p.Arg679Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,326,878 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: DLG4 NM_001365.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.618
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3807283).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365.5. 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.2036G>T	p.Arg679Leu	missense	Exon 20 of 22	NP_001356.1	P78352-2
	DLG4	NM_001321075.3	MANE Select	c.1907G>T	p.Arg636Leu	missense	Exon 18 of 20	NP_001308004.1	P78352-1
	DLG4	NM_001321074.1		c.2027G>T	p.Arg676Leu	missense	Exon 20 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.2036G>T	p.Arg679Leu	missense	Exon 20 of 22	ENSP00000497806.3	P78352-2
	DLG4	ENST00000399506.9	TSL:2 MANE Select	c.1907G>T	p.Arg636Leu	missense	Exon 18 of 20	ENSP00000382425.2	P78352-1
	DLG4	ENST00000399510.8	TSL:1	c.2027G>T	p.Arg676Leu	missense	Exon 20 of 22	ENSP00000382428.3	B9EGL1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1326878 Hom.: 0 Cov.: 31 AF XY: 0.00000307 AC XY: 2 AN XY: 651970

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28220

American (AMR) AF: 0.00 AC: 0 AN: 27580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19758

East Asian (EAS) AF: 0.00 AC: 0 AN: 33920

South Asian (SAS) AF: 0.0000152 AC: 1 AN: 65604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5198

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1043470

Other (OTH) AF: 0.00 AC: 0 AN: 54090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	0.93
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.29	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.62
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.059	T
Polyphen		0.99	D
Vest4		0.49
MutPred		0.55		Loss of MoRF binding (P = 0.0441)
MVP		0.62
MPC		2.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.17
gMVP		0.98
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1488126978; hg19: chr17-7095281;