X-70445367-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021120.4(DLG3):c.166T>A(p.Ser56Thr) 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 (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17651418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.166T>A	p.Ser56Thr	missense_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3	c.166T>A	p.Ser56Thr	missense_variant	1/20
DLG3	XM_011530883.2	c.166T>A	p.Ser56Thr	missense_variant	1/19
DLG3	XM_006724626.3	c.166T>A	p.Ser56Thr	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.166T>A	p.Ser56Thr	missense_variant	1/19	1	NM_021120.4
DLG3	ENST00000194900.8	c.166T>A	p.Ser56Thr	missense_variant	1/21	5		P1
DLG3	ENST00000463252.5	n.232T>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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1380473). This variant has not been reported in the literature in individuals affected with DLG3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 56 of the DLG3 protein (p.Ser56Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.054	T;T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.77	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.058
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.12	.;B
Vest4		0.29
MutPred		0.47		Gain of glycosylation at S55 (P = 0.0645);Gain of glycosylation at S55 (P = 0.0645);
MVP		0.47
MPC		0.77
ClinPred		0.35	T
GERP RS		3.7
Varity_R		0.25
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69665217;