rs535820581

Variant names:

• chrX-70499980-C-T
• rs535820581
• NM_021120.4:c.2076C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_021120.4(DLG3):​c.2076C>T​(p.Ile692Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,208,863 control chromosomes in the GnomAD database, including 8 homozygotes. There are 395 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 15 hem., cov: 22)
  • Exomes 𝑓: 0.00065 (8 hom. 380 hem.)
• Consequence: DLG3 NM_021120.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.51
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-70499980-C-T is Benign according to our data. Variant chrX-70499980-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210851.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 15 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	NM_021120.4	MANE Select	c.2076C>T	p.Ile692Ile	synonymous	Exon 16 of 19	NP_066943.2
	DLG3	NM_020730.3		c.1161C>T	p.Ile387Ile	synonymous	Exon 11 of 14	NP_065781.1
	DLG3	NM_001166278.2		c.723C>T	p.Ile241Ile	synonymous	Exon 9 of 12	NP_001159750.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	ENST00000374360.8	TSL:1 MANE Select	c.2076C>T	p.Ile692Ile	synonymous	Exon 16 of 19	ENSP00000363480.3
	DLG3	ENST00000374355.8	TSL:1	c.1161C>T	p.Ile387Ile	synonymous	Exon 11 of 14	ENSP00000363475.3
	DLG3	ENST00000194900.8	TSL:5	c.2172C>T	p.Ile724Ile	synonymous	Exon 18 of 21	ENSP00000194900.4

Frequencies

GnomAD3 genomes AF: 0.000260 AC: 29 AN: 111379 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000667

GnomAD2 exomes AF: 0.00133 AC: 243 AN: 182607 AF XY: 0.00191

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000650 AC: 713 AN: 1097431 Hom.: 8 Cov.: 31 AF XY: 0.00105 AC XY: 380 AN XY: 362799

African (AFR) AF: 0.00 AC: 0 AN: 26387

American (AMR) AF: 0.0000284 AC: 1 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.0123 AC: 666 AN: 54023

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841514

Other (OTH) AF: 0.000781 AC: 36 AN: 46077

GnomAD4 genome AF: 0.000260 AC: 29 AN: 111432 Hom.: 0 Cov.: 22 AF XY: 0.000446 AC XY: 15 AN XY: 33642

African (AFR) AF: 0.00 AC: 0 AN: 30666

American (AMR) AF: 0.00 AC: 0 AN: 10487

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.0109 AC: 28 AN: 2579

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6027

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53073

Other (OTH) AF: 0.000659 AC: 1 AN: 1518

Alfa AF: 0.000217 Hom.: 2

Bravo AF: 0.000110

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.32
DANN	Benign	0.52
PhyloP100		-2.5
Mutation Taster		=98/2	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: rs535820581; hg19: chrX-69719830; COSMIC: COSV52085574; COSMIC: COSV52085574;