rs2281868

chrX-70448613-A-GchrX-70448613-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021120.4(DLG3):c.358-300A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 1,052,357 control chromosomes in the GnomAD database, including 81,333 homozygotes. There are 163,249 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (13737 hom., 17533 hem., cov: 21)
  • Exomes 𝑓: 0.47 (81333 hom. 163249 hem.)
  • Failed GnomAD Quality Control
• Consequence: DLG3 NM_021120.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.982

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.1137406E-5).
• BP6: Variant X-70448613-A-G is Benign according to our data. Variant chrX-70448613-A-G is described in ClinVar as [Benign]. Clinvar id is 1277416.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-70448613-A-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.358-300A>G		intron_variant		ENST00000374360.8
DLG3	XM_006724625.3	c.358-300A>G		intron_variant
DLG3	XM_006724626.3	c.358-300A>G		intron_variant
DLG3	XM_011530883.2	c.358-300A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.358-300A>G		intron_variant		1	NM_021120.4
DLG3	ENST00000194900.8	c.391A>G	p.Thr131Ala	missense_variant	2/21	5		P1
DLG3	ENST00000463252.5	n.424-300A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.572 AC: 62234 AN: 108749 Hom.: 13723 Cov.: 21 AF XY: 0.563 AC XY: 17482 AN XY: 31073

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.480

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.591

GnomAD3 exomes AF: 0.520 AC: 57081 AN: 109721 Hom.: 10007 AF XY: 0.512 AC XY: 20397 AN XY: 39851

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.612

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.331

Gnomad SAS exome AF: 0.531

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.474 AC: 498640 AN: 1052357 Hom.: 81333 Cov.: 32 AF XY: 0.475 AC XY: 163249 AN XY: 343961

Gnomad4 AFR exome AF: 0.794

Gnomad4 AMR exome AF: 0.617

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.530

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.489

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.573 AC: 62298 AN: 108803 Hom.: 13737 Cov.: 21 AF XY: 0.563 AC XY: 17533 AN XY: 31137

Gnomad4 AFR AF: 0.794

Gnomad4 AMR AF: 0.607

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.464

Gnomad4 OTH AF: 0.595

Alfa AF: 0.498 Hom.: 9506

Bravo AF: 0.592

TwinsUK AF: 0.450 AC: 1668

ALSPAC AF: 0.451 AC: 1302

ExAC AF: 0.485 AC: 11439

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.95	T
BayesDel_noAF	Benign	-0.99
Cadd	Benign	12
Dann	Benign	0.67
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.000041	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.043
Sift	Benign	0.23	T
Sift4G	Benign	0.42	T
Vest4		0.017
ClinPred		0.014	T
GERP RS		2.5

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

LitVar

Other links and lift over

dbSNP: rs2281868; hg19: chrX-69668463; COSMIC: COSV52080607; COSMIC: COSV52080607;