X-70445354-TG-T

Variant names:

• chrX-70445354-TG-T
• NM_021120.4:c.158delG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_021120.4(DLG3):​c.158delG​(p.Gly53AlafsTer68) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DLG3 NM_021120.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.16

Genes affected

DLG3 (HGNC:2902): (discs large MAGUK scaffold protein 3) This gene encodes a member of the membrane-associated guanylate kinase protein family. The encoded protein may play a role in clustering of NMDA receptors at excitatory synapses. It may also negatively regulate cell proliferation through interaction with the C-terminal region of the adenomatosis polyposis coli tumor suppressor protein. Mutations in this gene have been associated with X-linked cognitive disability. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 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 X-70445354-TG-T is Pathogenic according to our data. Variant chrX-70445354-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 3272237.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG3	NM_021120.4	c.158delG	p.Gly53AlafsTer68	frameshift_variant	Exon 1 of 19	ENST00000374360.8	NP_066943.2
DLG3	XM_006724625.3	c.158delG	p.Gly53AlafsTer68	frameshift_variant	Exon 1 of 20		XP_006724688.1
DLG3	XM_011530883.2	c.158delG	p.Gly53AlafsTer68	frameshift_variant	Exon 1 of 19		XP_011529185.1
DLG3	XM_006724626.3	c.158delG	p.Gly53AlafsTer68	frameshift_variant	Exon 1 of 20		XP_006724689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG3	ENST00000374360.8	c.158delG	p.Gly53AlafsTer68	frameshift_variant	Exon 1 of 19	1	NM_021120.4	ENSP00000363480.3
DLG3	ENST00000194900.8	c.158delG	p.Gly53AlafsTer74	frameshift_variant	Exon 1 of 21	5		ENSP00000194900.4
DLG3	ENST00000463252.5	n.224delG		non_coding_transcript_exon_variant	Exon 1 of 19	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1059465 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 345133

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.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 17, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.158delG (p.G53Afs*68) alteration, located in exon 1 (coding exon 1) of the DLG3 gene, consists of a deletion of one nucleotide at position 158, causing a translational frameshift with a predicted alternate stop codon after 68 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: chrX-69665204;