rs2281868

Variant names:

• chrX-70448613-A-G
• rs2281868
• NM_021120.4:c.358-300A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-70448613-A-G
• chrX-70448613-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.982
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 90

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1277416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021120.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	NM_021120.4	MANE Select	c.358-300A>G		intron	N/A	NP_066943.2	Q92796-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	ENST00000374360.8	TSL:1 MANE Select	c.358-300A>G		intron	N/A	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000194900.8	TSL:5	c.391A>G	p.Thr131Ala	missense	Exon 2 of 21	ENSP00000194900.4	Q5JUW8
	DLG3	ENST00000949779.1		c.358-300A>G		intron	N/A	ENSP00000619838.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 62234 AN: 108749 Hom.: 13723 Cov.: 21

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

GnomAD2 exomes AF: 0.520 AC: 57081 AN: 109721 AF XY: 0.512

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 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

African (AFR) AF: 0.794 AC: 19775 AN: 24899

American (AMR) AF: 0.617 AC: 17215 AN: 27904

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 9488 AN: 18630

East Asian (EAS) AF: 0.322 AC: 8725 AN: 27128

South Asian (SAS) AF: 0.530 AC: 26411 AN: 49847

European-Finnish (FIN) AF: 0.549 AC: 20226 AN: 36839

Middle Eastern (MID) AF: 0.534 AC: 2181 AN: 4087

European-Non Finnish (NFE) AF: 0.456 AC: 372909 AN: 818651

Other (OTH) AF: 0.489 AC: 21710 AN: 44372

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

African (AFR) AF: 0.794 AC: 23608 AN: 29734

American (AMR) AF: 0.607 AC: 6284 AN: 10353

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1331 AN: 2599

East Asian (EAS) AF: 0.325 AC: 1106 AN: 3406

South Asian (SAS) AF: 0.520 AC: 1246 AN: 2395

European-Finnish (FIN) AF: 0.550 AC: 3150 AN: 5730

Middle Eastern (MID) AF: 0.459 AC: 96 AN: 209

European-Non Finnish (NFE) AF: 0.464 AC: 24259 AN: 52243

Other (OTH) AF: 0.595 AC: 876 AN: 1473

Alfa AF: 0.484 Hom.: 14033

Bravo AF: 0.592

TwinsUK AF: 0.450 AC: 1668

ALSPAC AF: 0.451 AC: 1302

ExAC AF: 0.485 AC: 11439

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
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
PhyloP100		0.98
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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