Variant X-70445397-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021120.4(DLG3):c.196A>C(p.Thr66Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. T66I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 24)

Failed GnomAD Quality Control

Consequence

DLG3
NM_021120.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.894

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.189859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DLG3	NM_021120.4 linkuse as main transcript	c.196A>C	p.Thr66Pro	missense_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3 linkuse as main transcript	c.196A>C	p.Thr66Pro	missense_variant	1/20
DLG3	XM_011530883.2 linkuse as main transcript	c.196A>C	p.Thr66Pro	missense_variant	1/19
DLG3	XM_006724626.3 linkuse as main transcript	c.196A>C	p.Thr66Pro	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8 linkuse as main transcript	c.196A>C	p.Thr66Pro	missense_variant	1/19	1	NM_021120.4		Q92796-1
DLG3	ENST00000194900.8 linkuse as main transcript	c.196A>C	p.Thr66Pro	missense_variant	1/21	5		P1
DLG3	ENST00000463252.5 linkuse as main transcript	n.262A>C		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111995

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34315

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

111995

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34315

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.196A>C (p.T66P) alteration is located in exon 1 (coding exon 1) of the DLG3 gene. This alteration results from a A to C substitution at nucleotide position 196, causing the threonine (T) at amino acid position 66 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Benign

0.85

DEOGEN2

Benign

0.046

T;T

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.92

N;N

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.35

N;N

REVEL

Benign

0.053

Sift

Benign

0.25

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.13

.;B

Vest4

0.23

MutPred

0.42

Loss of phosphorylation at T66 (P = 0.0298);Loss of phosphorylation at T66 (P = 0.0298);

MVP

0.60

MPC

1.4

ClinPred

0.91

GERP RS

2.6

Varity_R

0.17

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over