X-70445394-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021120.4(DLG3):c.193G>A(p.Ala65Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000845 in 1,183,133 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000084 (0 hom. 2 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.62

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029107988).
• BP6: Variant X-70445394-G-A is Benign according to our data. Variant chrX-70445394-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3082778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000841 (9/1070104) while in subpopulation EAS AF= 0.000319 (9/28252). AF 95% confidence interval is 0.000166. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.193G>A	p.Ala65Thr	missense_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3	c.193G>A	p.Ala65Thr	missense_variant	1/20
DLG3	XM_011530883.2	c.193G>A	p.Ala65Thr	missense_variant	1/19
DLG3	XM_006724626.3	c.193G>A	p.Ala65Thr	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.193G>A	p.Ala65Thr	missense_variant	1/19	1	NM_021120.4
DLG3	ENST00000194900.8	c.193G>A	p.Ala65Thr	missense_variant	1/21	5		P1
DLG3	ENST00000463252.5	n.259G>A		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes AF: 0.00000885 AC: 1 AN: 113029 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35197

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000719 AC: 9 AN: 125181 Hom.: 0 AF XY: 0.0000510 AC XY: 2 AN XY: 39195

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000915

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000841 AC: 9 AN: 1070104 Hom.: 0 Cov.: 32 AF XY: 0.00000575 AC XY: 2 AN XY: 348078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000319

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000885 AC: 1 AN: 113029 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35197

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000523 AC: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.63
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.048	T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.023	D;T
Sift4G	Benign	0.24	T;T
Polyphen		0.26	.;B
Vest4		0.29
MutPred		0.36		Gain of glycosylation at A65 (P = 0.0031);Gain of glycosylation at A65 (P = 0.0031);
MVP		0.52
MPC		0.93
ClinPred		0.11	T
GERP RS		3.7
Varity_R		0.19
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs760217541; hg19: chrX-69665244;