rs11797456

Variant names:

• chrX-70445505-G-A
• rs11797456
• NM_021120.4:c.304G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_021120.4(DLG3):​c.304G>A​(p.Gly102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,191,109 control chromosomes in the GnomAD database, including 14 homozygotes. There are 2,067 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., 95 hem., cov: 24)
  • Exomes 𝑓: 0.0058 (14 hom. 1972 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.40
• Publications: 5 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004940212).
• BP6: Variant X-70445505-G-A is Benign according to our data. Variant chrX-70445505-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 95 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	NM_021120.4	MANE Select	c.304G>A	p.Gly102Ser	missense	Exon 1 of 19	NP_066943.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	ENST00000374360.8	TSL:1 MANE Select	c.304G>A	p.Gly102Ser	missense	Exon 1 of 19	ENSP00000363480.3
	DLG3	ENST00000194900.8	TSL:5	c.304G>A	p.Gly102Ser	missense	Exon 1 of 21	ENSP00000194900.4
	DLG3	ENST00000463252.5	TSL:5	n.370G>A		non_coding_transcript_exon	Exon 1 of 19

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 438 AN: 112803 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000902

Gnomad AMI AF: 0.0117

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.000376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00271

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00691

Gnomad OTH AF: 0.00261

GnomAD2 exomes AF: 0.00333 AC: 458 AN: 137498 AF XY: 0.00329

Gnomad AFR exome AF: 0.000832

Gnomad AMR exome AF: 0.000756

Gnomad ASJ exome AF: 0.000760

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00179

Gnomad NFE exome AF: 0.00672

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00579 AC: 6245 AN: 1078256 Hom.: 14 Cov.: 32 AF XY: 0.00563 AC XY: 1972 AN XY: 350430

African (AFR) AF: 0.000423 AC: 11 AN: 25994

American (AMR) AF: 0.000766 AC: 25 AN: 32657

Ashkenazi Jewish (ASJ) AF: 0.000949 AC: 18 AN: 18971

East Asian (EAS) AF: 0.0000344 AC: 1 AN: 29078

South Asian (SAS) AF: 0.000875 AC: 45 AN: 51419

European-Finnish (FIN) AF: 0.00251 AC: 96 AN: 38182

Middle Eastern (MID) AF: 0.000974 AC: 4 AN: 4106

European-Non Finnish (NFE) AF: 0.00699 AC: 5818 AN: 832506

Other (OTH) AF: 0.00501 AC: 227 AN: 45343

GnomAD4 genome AF: 0.00388 AC: 438 AN: 112853 Hom.: 0 Cov.: 24 AF XY: 0.00271 AC XY: 95 AN XY: 35001

African (AFR) AF: 0.000900 AC: 28 AN: 31125

American (AMR) AF: 0.00101 AC: 11 AN: 10848

Ashkenazi Jewish (ASJ) AF: 0.000376 AC: 1 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.00 AC: 0 AN: 2756

European-Finnish (FIN) AF: 0.00271 AC: 17 AN: 6279

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.00692 AC: 368 AN: 53216

Other (OTH) AF: 0.00258 AC: 4 AN: 1551

Alfa AF: 0.00523 Hom.: 227

Bravo AF: 0.00328

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.000806 AC: 3

ESP6500EA AF: 0.00443 AC: 29

ExAC AF: 0.00295 AC: 346

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (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	0.061
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N
PhyloP100		3.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.064
Sift	Benign	0.21	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.043
MVP		0.38
MPC		0.86
ClinPred		0.0056	T
GERP RS		3.8
Varity_R		0.094
gMVP		0.48
Mutation Taster		=98/2	polymorphism (auto)

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: rs11797456; hg19: chrX-69665355; COSMIC: COSV99530293;