17-7191339-T-G

Position:

• chr17-7191339-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001321075.3(DLG4):​c.1996A>C​(p.Thr666Pro) 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: 4.66

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DLG4. . Gene score misZ 4.933 (greater than the threshold 3.09). Trascript score misZ 4.8337 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, intellectual developmental disorder 62.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.1996A>C	p.Thr666Pro	missense_variant	19/20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.1996A>C	p.Thr666Pro	missense_variant	19/20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.8	c.2125A>C	p.Thr709Pro	missense_variant	21/22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2095A>C	p.Thr699Pro	missense_variant	19/20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1816A>C	p.Thr606Pro	missense_variant	18/19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.*11A>C		non_coding_transcript_exon_variant	20/21	2		ENSP00000467897.2
DLG4	ENST00000491753.2	n.*11A>C		3_prime_UTR_variant	20/21	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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;.;T;T;T;.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.5	.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.1	.;D;D;.;.;.;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.047	.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0050	.;D;D;.;.;.;.;.
Polyphen		0.87	P;.;D;.;P;.;.;.
Vest4		0.44, 0.42
MutPred		0.63		.;.;Loss of phosphorylation at T666 (P = 0.0516);.;.;.;.;.;
MVP		0.65
MPC		2.5
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7094658;