17-7190742-G-C

Variant names:

• chr17-7190742-G-C
• NM_001321075.3:c.2141C>G

Variant summary

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

The NM_001321075.3(DLG4):​c.2141C>G​(p.Pro714Arg) variant causes a missense change involving the alteration of a non-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: 3.55
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.2141C>G	p.Pro714Arg	missense_variant	Exon 20 of 20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.2141C>G	p.Pro714Arg	missense_variant	Exon 20 of 20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.9	c.2270C>G	p.Pro757Arg	missense_variant	Exon 22 of 22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2240C>G	p.Pro747Arg	missense_variant	Exon 20 of 20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1961C>G	p.Pro654Arg	missense_variant	Exon 19 of 19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.*156C>G		non_coding_transcript_exon_variant	Exon 21 of 21	2		ENSP00000467897.2
DLG4	ENST00000491753.2	n.*156C>G		3_prime_UTR_variant	Exon 21 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

May 26, 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;D;T;T;.;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;.;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;.;M;.;.;.;.;.
PhyloP100		3.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.3	.;D;D;.;.;.;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.021	.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.043	.;D;D;.;.;.;.;.
Polyphen		1.0	D;.;B;.;B;.;.;.
Vest4		0.45, 0.44
MutPred		0.55		.;.;Gain of MoRF binding (P = 2e-04);.;.;.;.;.;
MVP		0.59
MPC		2.3
ClinPred		0.91	D
GERP RS		4.1
Varity_R		0.096
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

hg19: chr17-7094061;