17-7192979-G-A

Position:

• chr17-7192979-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001321075.3(DLG4):​c.1832C>T​(p.Thr611Ile) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DLG4 NM_001321075.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.98

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a domain Guanylate kinase-like (size 175) in uniprot entity DLG4_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_001321075.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DLG4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 17-7192979-G-A is Pathogenic according to our data. Variant chr17-7192979-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1329903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7192979-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG4	NM_001321075.3	c.1832C>T	p.Thr611Ile	missense_variant	17/20	ENST00000399506.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG4	ENST00000399506.9	c.1832C>T	p.Thr611Ile	missense_variant	17/20	2	NM_001321075.3	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder 62 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Dec 21, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Tumer Group, Copenhagen University Hospital, Rigshospitalet	Feb 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
Polyphen		0.99	D;.;D;.;D;.;.;.;.
Vest4		0.93, 0.93
MutPred		0.84		.;.;Loss of disorder (P = 0.0669);.;.;.;.;.;.;
MVP		0.80
MPC		2.4
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.12
gMVP		1.0

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: chr17-7096298;