chrX-70445353-A-G

Variant names:

• chrX-70445353-A-G
• rs763609801
• NM_021120.4:c.152A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021120.4(DLG3):​c.152A>G​(p.Tyr51Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000884 in 113,147 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y51S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 24)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61
• 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 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39622405).

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.152A>G	p.Tyr51Cys	missense	Exon 1 of 19	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.152A>G	p.Tyr51Cys	missense	Exon 1 of 19	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000194900.8	TSL:5	c.152A>G	p.Tyr51Cys	missense	Exon 1 of 21	ENSP00000194900.4	Q5JUW8
	DLG3	ENST00000949779.1		c.152A>G	p.Tyr51Cys	missense	Exon 1 of 20	ENSP00000619838.1

Frequencies

GnomAD3 genomes AF: 0.00000884 AC: 1 AN: 113147 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000320

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000884 AC: 1 AN: 113147 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 35317

African (AFR) AF: 0.0000320 AC: 1 AN: 31212

American (AMR) AF: 0.00 AC: 0 AN: 10890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2817

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53255

Other (OTH) AF: 0.00 AC: 0 AN: 1532

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.95	N
REVEL	Uncertain	0.35
Sift	Benign	0.043	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.93	P
Vest4		0.43
MutPred		0.68		Loss of phosphorylation at Y51 (P = 0.0153)
MVP		0.86
MPC		1.5
ClinPred		0.70	D
GERP RS		3.7
PromoterAI		0.037	Neutral
Varity_R		0.28
gMVP		0.69
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs763609801; hg19: chrX-69665203;