rs144225009

Variant names:

• chrX-70449379-C-T
• rs144225009
• NM_021120.4:c.429C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_021120.4(DLG3):​c.429C>T​(p.Phe143Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,209,847 control chromosomes in the GnomAD database, including 2 homozygotes. There are 653 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 38 hem., cov: 22)
  • Exomes 𝑓: 0.0018 (2 hom. 615 hem.)
• Consequence: DLG3 NM_021120.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.53
• 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 (BayesDel_noAF=-0.43).
• BP6: Variant X-70449379-C-T is Benign according to our data. Variant chrX-70449379-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210852.
• BP7: Synonymous conserved (PhyloP=2.53 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 38 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.429C>T	p.Phe143Phe	synonymous	Exon 3 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.429C>T	p.Phe143Phe	synonymous	Exon 3 of 19	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000194900.8	TSL:5	c.483C>T	p.Phe161Phe	synonymous	Exon 4 of 21	ENSP00000194900.4	Q5JUW8
	DLG3	ENST00000949779.1		c.429C>T	p.Phe143Phe	synonymous	Exon 3 of 20	ENSP00000619838.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 137 AN: 111598 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000378

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.00134 AC: 246 AN: 183102 AF XY: 0.00133

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00182 AC: 2002 AN: 1098195 Hom.: 2 Cov.: 32 AF XY: 0.00169 AC XY: 615 AN XY: 363555

African (AFR) AF: 0.000114 AC: 3 AN: 26402

American (AMR) AF: 0.000454 AC: 16 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54148

European-Finnish (FIN) AF: 0.00188 AC: 76 AN: 40528

Middle Eastern (MID) AF: 0.00411 AC: 17 AN: 4137

European-Non Finnish (NFE) AF: 0.00216 AC: 1818 AN: 842085

Other (OTH) AF: 0.00152 AC: 70 AN: 46097

GnomAD4 genome AF: 0.00123 AC: 137 AN: 111652 Hom.: 0 Cov.: 22 AF XY: 0.00112 AC XY: 38 AN XY: 33806

African (AFR) AF: 0.000261 AC: 8 AN: 30694

American (AMR) AF: 0.000378 AC: 4 AN: 10583

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2598

European-Finnish (FIN) AF: 0.00133 AC: 8 AN: 6037

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00216 AC: 115 AN: 53123

Other (OTH) AF: 0.00131 AC: 2 AN: 1522

Alfa AF: 0.00108 Hom.: 13

Bravo AF: 0.000910

EpiCase AF: 0.00207

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		2.5
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144225009; hg19: chrX-69669229;