rs11797456

chrX-70445505-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021120.4(DLG3):c.304G>A(p.Gly102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,191,109 control chromosomes in the GnomAD database, including 14 homozygotes. There are 2,067 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., 95 hem., cov: 24)
  • Exomes 𝑓: 0.0058 (14 hom. 1972 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.40

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004940212).
• BP6: Variant X-70445505-G-A is Benign according to our data. Variant chrX-70445505-G-A is described in ClinVar as [Benign]. Clinvar id is 96020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70445505-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00388 (438/112853) while in subpopulation NFE AF= 0.00692 (368/53216). AF 95% confidence interval is 0.00633. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 95 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.304G>A	p.Gly102Ser	missense_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3	c.304G>A	p.Gly102Ser	missense_variant	1/20
DLG3	XM_011530883.2	c.304G>A	p.Gly102Ser	missense_variant	1/19
DLG3	XM_006724626.3	c.304G>A	p.Gly102Ser	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.304G>A	p.Gly102Ser	missense_variant	1/19	1	NM_021120.4
DLG3	ENST00000194900.8	c.304G>A	p.Gly102Ser	missense_variant	1/21	5		P1
DLG3	ENST00000463252.5	n.370G>A		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 438 AN: 112803 Hom.: 0 Cov.: 24 AF XY: 0.00272 AC XY: 95 AN XY: 34941

Gnomad AFR AF: 0.000902

Gnomad AMI AF: 0.0117

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.000376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00271

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00691

Gnomad OTH AF: 0.00261

GnomAD3 exomes AF: 0.00333 AC: 458 AN: 137498 Hom.: 1 AF XY: 0.00329 AC XY: 140 AN XY: 42606

Gnomad AFR exome AF: 0.000832

Gnomad AMR exome AF: 0.000756

Gnomad ASJ exome AF: 0.000760

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00179

Gnomad NFE exome AF: 0.00672

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00579 AC: 6245 AN: 1078256 Hom.: 14 Cov.: 32 AF XY: 0.00563 AC XY: 1972 AN XY: 350430

Gnomad4 AFR exome AF: 0.000423

Gnomad4 AMR exome AF: 0.000766

Gnomad4 ASJ exome AF: 0.000949

Gnomad4 EAS exome AF: 0.0000344

Gnomad4 SAS exome AF: 0.000875

Gnomad4 FIN exome AF: 0.00251

Gnomad4 NFE exome AF: 0.00699

Gnomad4 OTH exome AF: 0.00501

GnomAD4 genome AF: 0.00388 AC: 438 AN: 112853 Hom.: 0 Cov.: 24 AF XY: 0.00271 AC XY: 95 AN XY: 35001

Gnomad4 AFR AF: 0.000900

Gnomad4 AMR AF: 0.00101

Gnomad4 ASJ AF: 0.000376

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00271

Gnomad4 NFE AF: 0.00692

Gnomad4 OTH AF: 0.00258

Alfa AF: 0.00563 Hom.: 226

Bravo AF: 0.00328

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.000806 AC: 3

ESP6500EA AF: 0.00443 AC: 29

ExAC AF: 0.00295 AC: 346

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2019

This alteration is classified as 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	0.061
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.039	T;T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.64	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.28	N;N
REVEL	Benign	0.064
Sift	Benign	0.21	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0010	.;B
Vest4		0.043
MVP		0.38
MPC		0.86
ClinPred		0.0056	T
GERP RS		3.8
Varity_R		0.094
gMVP		0.48

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: rs11797456; hg19: chrX-69665355; COSMIC: COSV99530293;