chrX-70453646-C-T

Variant names:

• chrX-70453646-C-T
• NM_021120.4:c.1155C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_021120.4(DLG3):​c.1155C>T​(p.Arg385Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,746 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: DLG3 NM_021120.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.699
• 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-AS1 (HGNC:40182): (DLG3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-70453646-C-T is Benign according to our data. Variant chrX-70453646-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1735152.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.699 with no splicing effect.

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.1155C>T	p.Arg385Arg	synonymous	Exon 8 of 19	NP_066943.2	Q92796-1
	DLG3	NM_020730.3		c.144C>T	p.Arg48Arg	synonymous	Exon 2 of 14	NP_065781.1	Q92796-2
	DLG3-AS1	NR_046586.1		n.84-340G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG3	ENST00000374360.8	TSL:1 MANE Select	c.1155C>T	p.Arg385Arg	synonymous	Exon 8 of 19	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000374355.8	TSL:1	c.144C>T	p.Arg48Arg	synonymous	Exon 2 of 14	ENSP00000363475.3	Q92796-2
	DLG3	ENST00000194900.8	TSL:5	c.1209C>T	p.Arg403Arg	synonymous	Exon 9 of 21	ENSP00000194900.4	Q5JUW8

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095746 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 1 AN XY: 361318

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26371

American (AMR) AF: 0.00 AC: 0 AN: 35033

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19312

East Asian (EAS) AF: 0.00 AC: 0 AN: 30174

South Asian (SAS) AF: 0.00 AC: 0 AN: 53535

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40405

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4055

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840844

Other (OTH) AF: 0.0000217 AC: 1 AN: 46017

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

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
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.2
DANN	Benign	0.74
PhyloP100		0.70

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

hg19: chrX-69673496;