17-7191933-TG-T

Variant names:

• chr17-7191933-TG-T
• NM_001321075.3:c.1935delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001321075.3(DLG4):​c.1935delC​(p.Ile646SerfsTer14) variant causes a frameshift 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 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 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.50
• 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: Pathogenic. The variant received 12 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 17-7191933-TG-T is Pathogenic according to our data. Variant chr17-7191933-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3901955.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.1935delC	p.Ile646SerfsTer14	frameshift_variant	Exon 18 of 20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.1935delC	p.Ile646SerfsTer14	frameshift_variant	Exon 18 of 20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.9	c.2064delC	p.Ile689SerfsTer14	frameshift_variant	Exon 20 of 22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2034delC	p.Ile679SerfsTer14	frameshift_variant	Exon 18 of 20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1755delC	p.Ile586SerfsTer14	frameshift_variant	Exon 17 of 19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.1996-576delC		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: 1334462 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 656448

African (AFR) AF: 0.00 AC: 0 AN: 28676

American (AMR) AF: 0.00 AC: 0 AN: 29656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19934

East Asian (EAS) AF: 0.00 AC: 0 AN: 34322

South Asian (SAS) AF: 0.00 AC: 0 AN: 68298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1046248

Other (OTH) AF: 0.00 AC: 0 AN: 54122

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder 62 Pathogenic:1

Sep 12, 2024

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PM2 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-7095252;