chr17-7191991-G-T

Position:

• chr17-7191991-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001321075.3(DLG4):​c.1878C>A​(p.Cys626Ter) variant causes a stop gained 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DLG4 NM_001321075.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.60

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7191991-G-T is Pathogenic according to our data. Variant chr17-7191991-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1329906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7191991-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.1878C>A	p.Cys626Ter	stop_gained	18/20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.1878C>A	p.Cys626Ter	stop_gained	18/20	2	NM_001321075.3	ENSP00000382425	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1295506 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 633862

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder 62 Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Tumer Group, Copenhagen University Hospital, Rigshospitalet	Feb 28, 2023	- -
Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Dec 21, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Jun 15, 2020	The c.1869C>A (p.Cys623Ter) variant in the DLG4 gene substitutes a cysteine residue to a stop codon at amino acid 623 in the guanylate kinase catalytic domain in coding exon 20 (out of 22 coding exons in total) of the DLG4 gene. This change results in premature protein truncation and is predicted to undergo nonsense mediated mRNA decay (NMD) Analyses of parental samples shows that neither the mother (PGL20-971_C1) nor the father (PGL20-971_C2) harbor this variant. Therefore, the variant appears to be a de novo change. This variant is absent in the Genome Aggregation Database (gnomAD), indicating that it is not a common benign variant in the populations represented therein. Heterozygous loss of function variants in DLG4 have been observed in multiple individuals with clinical features of Intellectual Developmental Disorder 62 (PMIDs: 27479843, 29460436). To the best of our knowledge this exact variant has not been reported in the literature or in ClinVar, however loss of function variants downstream of p.Cys623Ter have been reported to be disease causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	42
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.67	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.95
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: chr17-7095310;