chrX-70445292-G-A

Variant names:

• chrX-70445292-G-A
• rs771173179
• NM_021120.4:c.91G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_021120.4(DLG3):​c.91G>A​(p.Gly31Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,164,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 96 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G31G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.00029 (0 hom. 94 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.87
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14971825).
• BP6: Variant X-70445292-G-A is Benign according to our data. Variant chrX-70445292-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2346213.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 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.91G>A	p.Gly31Ser	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.91G>A	p.Gly31Ser	missense	Exon 1 of 19	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000194900.8	TSL:5	c.91G>A	p.Gly31Ser	missense	Exon 1 of 21	ENSP00000194900.4	Q5JUW8
	DLG3	ENST00000949779.1		c.91G>A	p.Gly31Ser	missense	Exon 1 of 20	ENSP00000619838.1

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 16 AN: 113351 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000319

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: 0.000263

Gnomad OTH AF: 0.000651

GnomAD2 exomes AF: 0.000128 AC: 13 AN: 101387 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000516

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000285 AC: 300 AN: 1050833 Hom.: 0 Cov.: 31 AF XY: 0.000274 AC XY: 94 AN XY: 343209

African (AFR) AF: 0.00 AC: 0 AN: 25013

American (AMR) AF: 0.0000714 AC: 2 AN: 28026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18623

East Asian (EAS) AF: 0.00 AC: 0 AN: 27278

South Asian (SAS) AF: 0.00 AC: 0 AN: 49927

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3891

European-Non Finnish (NFE) AF: 0.000360 AC: 295 AN: 819886

Other (OTH) AF: 0.0000676 AC: 3 AN: 44365

GnomAD4 genome AF: 0.000141 AC: 16 AN: 113351 Hom.: 0 Cov.: 24 AF XY: 0.0000564 AC XY: 2 AN XY: 35491

African (AFR) AF: 0.0000319 AC: 1 AN: 31318

American (AMR) AF: 0.00 AC: 0 AN: 10879

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6311

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53315

Other (OTH) AF: 0.000651 AC: 1 AN: 1537

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.000113

ExAC AF: 0.0000775 AC: 7

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		6.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.28	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.27
MVP		0.73
MPC		0.71
ClinPred		0.25	T
GERP RS		3.8
PromoterAI		-0.020	Neutral
Varity_R		0.38
gMVP		0.40
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771173179; hg19: chrX-69665142;