chrX-70445206-A-C

Variant names:

• chrX-70445206-A-C
• rs1410761133
• NM_021120.4:c.5A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021120.4(DLG3):​c.5A>C​(p.His2Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,043,050 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000096 (0 hom. 4 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.84
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 4 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.5A>C	p.His2Pro	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.5A>C	p.His2Pro	missense	Exon 1 of 19	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000194900.8	TSL:5	c.5A>C	p.His2Pro	missense	Exon 1 of 21	ENSP00000194900.4	Q5JUW8
	DLG3	ENST00000949779.1		c.5A>C	p.His2Pro	missense	Exon 1 of 20	ENSP00000619838.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000101 AC: 1 AN: 99170 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: 0.0000278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 10 AN: 1043050 Hom.: 0 Cov.: 30 AF XY: 0.0000118 AC XY: 4 AN XY: 337816

African (AFR) AF: 0.00 AC: 0 AN: 24988

American (AMR) AF: 0.00 AC: 0 AN: 27966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18573

East Asian (EAS) AF: 0.00 AC: 0 AN: 27356

South Asian (SAS) AF: 0.00 AC: 0 AN: 49848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3314

European-Non Finnish (NFE) AF: 0.0000123 AC: 10 AN: 815437

Other (OTH) AF: 0.00 AC: 0 AN: 44116

GnomAD4 genome Cov.: 24

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability, X-linked 90 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.53
MutPred		0.32		Gain of catalytic residue at H2 (P = 0.0066)
MVP		0.79
MPC		1.1
ClinPred		0.83	D
GERP RS		4.0
PromoterAI		0.076	Neutral
Varity_R		0.56
gMVP		0.73
Mutation Taster		=53/47	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: rs1410761133; hg19: chrX-69665056;