chrX-70445353-A-T

Variant names:

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

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.152A>T​(p.Tyr51Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000189 in 1,059,209 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. 14/21 in silico tools predict 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: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25669193).

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>T	p.Tyr51Phe	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>T	p.Tyr51Phe	missense	Exon 1 of 19	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000194900.8	TSL:5	c.152A>T	p.Tyr51Phe	missense	Exon 1 of 21	ENSP00000194900.4	Q5JUW8
	DLG3	ENST00000949779.1		c.152A>T	p.Tyr51Phe	missense	Exon 1 of 20	ENSP00000619838.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000899 AC: 1 AN: 111250 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000238

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000189 AC: 2 AN: 1059209 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 345049

African (AFR) AF: 0.00 AC: 0 AN: 25337

American (AMR) AF: 0.00 AC: 0 AN: 29551

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18685

East Asian (EAS) AF: 0.00 AC: 0 AN: 27788

South Asian (SAS) AF: 0.00 AC: 0 AN: 50342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34919

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4030

European-Non Finnish (NFE) AF: 0.00000243 AC: 2 AN: 823931

Other (OTH) AF: 0.00 AC: 0 AN: 44626

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.051	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.18
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.033	D
Polyphen		0.50	P
Vest4		0.37
MutPred		0.67		Loss of phosphorylation at Y51 (P = 0.0153)
MVP		0.78
MPC		0.88
ClinPred		0.55	D
GERP RS		3.7
PromoterAI		0.041	Neutral
Varity_R		0.27
gMVP		0.46
Mutation Taster		=94/6	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: rs763609801; hg19: chrX-69665203;