NM_021120.4:c.1360C>T

Variant names:

• chrX-70454271-C-T
• rs769457554
• NM_021120.4:c.1360C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_021120.4(DLG3):​c.1360C>T​(p.Arg454Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,209,698 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.375
• 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-AS1 (HGNC:40182): (DLG3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2660221).
• BS2: High Hemizygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	NM_021120.4	MANE Select	c.1360C>T	p.Arg454Trp	missense	Exon 9 of 19	NP_066943.2	Q92796-1
	DLG3	NM_020730.3		c.349C>T	p.Arg117Trp	missense	Exon 3 of 14	NP_065781.1	Q92796-2
	DLG3-AS1	NR_046586.1		n.84-965G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	ENST00000374360.8	TSL:1 MANE Select	c.1360C>T	p.Arg454Trp	missense	Exon 9 of 19	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000374355.8	TSL:1	c.349C>T	p.Arg117Trp	missense	Exon 3 of 14	ENSP00000363475.3	Q92796-2
	DLG3	ENST00000194900.8	TSL:5	c.1414C>T	p.Arg472Trp	missense	Exon 10 of 21	ENSP00000194900.4	Q5JUW8

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111844 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182629 AF XY: 0.0000149

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097854 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363212

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841922

Other (OTH) AF: 0.00 AC: 0 AN: 46076

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111844 Hom.: 0 Cov.: 24 AF XY: 0.0000588 AC XY: 2 AN XY: 34040

African (AFR) AF: 0.0000976 AC: 3 AN: 30727

American (AMR) AF: 0.00 AC: 0 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53176

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.38
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.56		Gain of catalytic residue at L452 (P = 0.0075)
MVP		0.48
MPC		1.8
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.49
gMVP		0.71
Mutation Taster		=72/28	polymorphism

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: rs769457554; hg19: chrX-69674121; COSMIC: COSV108742369; COSMIC: COSV108742369;