NM_001321075.3:c.2000A>G

Variant names:

• chr17-7191335-T-C
• NM_001321075.3:c.2000A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001321075.3(DLG4):​c.2000A>G​(p.Glu667Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 5.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.2000A>G	p.Glu667Gly	missense_variant	Exon 19 of 20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.2000A>G	p.Glu667Gly	missense_variant	Exon 19 of 20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.8	c.2129A>G	p.Glu710Gly	missense_variant	Exon 21 of 22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2099A>G	p.Glu700Gly	missense_variant	Exon 19 of 20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1820A>G	p.Glu607Gly	missense_variant	Exon 18 of 19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.*15A>G		non_coding_transcript_exon_variant	Exon 20 of 21	2		ENSP00000467897.2
DLG4	ENST00000491753.2	n.*15A>G		3_prime_UTR_variant	Exon 20 of 21	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 17, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	.;.;T;T;T;.;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	4.3	.;.;H;.;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.5	.;D;D;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.014	.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.016	.;D;D;.;.;.;.;.
Polyphen		0.74	P;.;B;.;B;.;.;.
Vest4		0.33, 0.33
MutPred		0.55		.;.;Gain of loop (P = 0);.;.;.;.;.;
MVP		0.67
MPC		2.4
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.12
gMVP		0.92

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7094654;