chr17-7191658-G-A

Variant names:

• chr17-7191658-G-A
• ENST00000489885.1:n.578C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001321075.3(DLG4):​c.1976+235C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DLG4 NM_001321075.3 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.226
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-7191658-G-A is Pathogenic according to our data. Variant chr17-7191658-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2498101.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.1976+235C>T		intron_variant	Intron 18 of 19	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.1976+235C>T		intron_variant	Intron 18 of 19	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.9	c.2105+235C>T		intron_variant	Intron 20 of 21			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2075+235C>T		intron_variant	Intron 18 of 19			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1796+235C>T		intron_variant	Intron 17 of 18			ENSP00000497647.1
DLG4	ENST00000491753.2	n.1996-300C>T		intron_variant	Intron 19 of 20	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 431882 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 225352

African (AFR) AF: 0.00 AC: 0 AN: 12168

American (AMR) AF: 0.00 AC: 0 AN: 18130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13176

East Asian (EAS) AF: 0.00 AC: 0 AN: 30610

South Asian (SAS) AF: 0.00 AC: 0 AN: 38356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1962

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 256084

Other (OTH) AF: 0.00 AC: 0 AN: 24886

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder 62 Pathogenic:1

Feb 28, 2023

Tumer Group, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.65
DANN	Benign	0.67
PhyloP100		-0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.91		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr17-7094977;