NM_021120.4:c.1172A>G

Variant names:

• chrX-70453663-A-G
• rs1555961844
• NM_021120.4:c.1172A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021120.4(DLG3):​c.1172A>G​(p.Lys391Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,095,863 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19908732).

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.1172A>G	p.Lys391Arg	missense	Exon 8 of 19	NP_066943.2
	DLG3	NM_020730.3		c.161A>G	p.Lys54Arg	missense	Exon 2 of 14	NP_065781.1
	DLG3-AS1	NR_046586.1		n.84-357T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	ENST00000374360.8	TSL:1 MANE Select	c.1172A>G	p.Lys391Arg	missense	Exon 8 of 19	ENSP00000363480.3
	DLG3	ENST00000374355.8	TSL:1	c.161A>G	p.Lys54Arg	missense	Exon 2 of 14	ENSP00000363475.3
	DLG3	ENST00000194900.8	TSL:5	c.1226A>G	p.Lys409Arg	missense	Exon 9 of 21	ENSP00000194900.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095863 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361367

African (AFR) AF: 0.00 AC: 0 AN: 26379

American (AMR) AF: 0.00 AC: 0 AN: 35048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19314

East Asian (EAS) AF: 0.00 AC: 0 AN: 30182

South Asian (SAS) AF: 0.00 AC: 0 AN: 53557

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840833

Other (OTH) AF: 0.0000217 AC: 1 AN: 46020

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.19
Sift	Benign	0.72	T
Sift4G	Benign	0.83	T
Polyphen		0.64	P
Vest4		0.25
MutPred		0.60		Loss of methylation at K391 (P = 0.0112)
MVP		0.79
MPC		1.6
ClinPred		0.76	D
GERP RS		3.3
Varity_R		0.16
gMVP		0.64
Mutation Taster		=96/4	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: rs1555961844; hg19: chrX-69673513;