rs797045525

Positions:

• chrX-70454318-TAGG-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_021120.4(DLG3):​c.1405+5_1405+7del variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000303 in 1,197,885 control chromosomes in the GnomAD database, including 2 homozygotes. There are 95 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., 45 hem., cov: 23)
  • Exomes 𝑓: 0.00018 (0 hom. 50 hem.)
• Consequence: DLG3 NM_021120.4 splice_donor_5th_base, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.18

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]

DLG3-AS1 (HGNC:40182): (DLG3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant X-70454318-TAGG-T is Benign according to our data. Variant chrX-70454318-TAGG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210850.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00154 (172/111692) while in subpopulation AFR AF= 0.00539 (166/30781). AF 95% confidence interval is 0.00472. There are 2 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.1405+5_1405+7del		splice_donor_5th_base_variant, intron_variant		ENST00000374360.8
DLG3-AS1	NR_109801.1	n.51-1015_51-1013del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.1405+5_1405+7del		splice_donor_5th_base_variant, intron_variant		1	NM_021120.4
DLG3-AS1	ENST00000431103.1	n.51-1015_51-1013del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 172 AN: 111637 Hom.: 2 Cov.: 23 AF XY: 0.00133 AC XY: 45 AN XY: 33847

Gnomad AFR AF: 0.00541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.000661

GnomAD3 exomes AF: 0.000504 AC: 91 AN: 180568 Hom.: 1 AF XY: 0.000292 AC XY: 19 AN XY: 65144

Gnomad AFR exome AF: 0.00632

Gnomad AMR exome AF: 0.000257

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000634

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000176 AC: 191 AN: 1086193 Hom.: 0 AF XY: 0.000142 AC XY: 50 AN XY: 351899

Gnomad4 AFR exome AF: 0.00623

Gnomad4 AMR exome AF: 0.000171

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.000350

GnomAD4 genome AF: 0.00154 AC: 172 AN: 111692 Hom.: 2 Cov.: 23 AF XY: 0.00133 AC XY: 45 AN XY: 33912

Gnomad4 AFR AF: 0.00539

Gnomad4 AMR AF: 0.000378

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.000652

Alfa AF: 0.00113 Hom.: 5

Bravo AF: 0.00186

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 01, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DLG3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 13

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045525; hg19: chrX-69674168;