X-70445328-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021120.4(DLG3):c.127G>A(p.Gly43Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.127G>A	p.Gly43Arg	missense_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3	c.127G>A	p.Gly43Arg	missense_variant	1/20
DLG3	XM_011530883.2	c.127G>A	p.Gly43Arg	missense_variant	1/19
DLG3	XM_006724626.3	c.127G>A	p.Gly43Arg	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.127G>A	p.Gly43Arg	missense_variant	1/19	1	NM_021120.4
DLG3	ENST00000194900.8	c.127G>A	p.Gly43Arg	missense_variant	1/21	5		P1
DLG3	ENST00000463252.5	n.193G>A		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 90 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 02, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (7 heterozygotes, 0 homozygotes, 0 hemizygotes) (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Benign	0.049	T;T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.075
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.20	T;D
Polyphen		1.0	.;D
Vest4		0.39
MutPred		0.27		Gain of methylation at G43 (P = 0.0076);Gain of methylation at G43 (P = 0.0076);
MVP		0.40
MPC		0.98
ClinPred		0.70	D
GERP RS		3.7
Varity_R		0.20
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69665178;