X-70445276-C-T

Variant names:

• chrX-70445276-C-T
• rs2086553526
• NM_021120.4:c.75C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_021120.4(DLG3):​c.75C>T​(p.Leu25Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000883 in 113,298 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L25L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DLG3 NM_021120.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.782
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP7: Synonymous conserved (PhyloP=0.782 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.75C>T	p.Leu25Leu	synonymous	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.75C>T	p.Leu25Leu	synonymous	Exon 1 of 19	ENSP00000363480.3	Q92796-1
	DLG3	ENST00000194900.8	TSL:5	c.75C>T	p.Leu25Leu	synonymous	Exon 1 of 21	ENSP00000194900.4	Q5JUW8
	DLG3	ENST00000949779.1		c.75C>T	p.Leu25Leu	synonymous	Exon 1 of 20	ENSP00000619838.1

Frequencies

GnomAD3 genomes AF: 0.00000883 AC: 1 AN: 113298 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1050523 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 343181

African (AFR) AF: 0.00 AC: 0 AN: 24980

American (AMR) AF: 0.00 AC: 0 AN: 27953

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18625

East Asian (EAS) AF: 0.00 AC: 0 AN: 27253

South Asian (SAS) AF: 0.00 AC: 0 AN: 49923

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3843

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819681

Other (OTH) AF: 0.00 AC: 0 AN: 44343

GnomAD4 genome AF: 0.00000883 AC: 1 AN: 113298 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 35484

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

African (AFR) AF: 0.00 AC: 0 AN: 31305

American (AMR) AF: 0.00 AC: 0 AN: 10877

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.00 AC: 0 AN: 2853

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53262

Other (OTH) AF: 0.00 AC: 0 AN: 1536

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.0
DANN	Benign	0.76
PhyloP100		0.78
PromoterAI		0.029	Neutral

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: rs2086553526; hg19: chrX-69665126;