X-70445329-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_021120.4(DLG3):c.128G>T(p.Gly43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,167,472 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 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. G43R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000020 ( 0 hom. 5 hem. )

Consequence

DLG3
NM_021120.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0098207).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000199 (21/1054004) while in subpopulation EAS AF= 0.000399 (11/27577). AF 95% confidence interval is 0.000223. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DLG3	NM_021120.4 linkuse as main transcript	c.128G>T	p.Gly43Val	missense_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3 linkuse as main transcript	c.128G>T	p.Gly43Val	missense_variant	1/20
DLG3	XM_011530883.2 linkuse as main transcript	c.128G>T	p.Gly43Val	missense_variant	1/19
DLG3	XM_006724626.3 linkuse as main transcript	c.128G>T	p.Gly43Val	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8 linkuse as main transcript	c.128G>T	p.Gly43Val	missense_variant	1/19	1	NM_021120.4		Q92796-1
DLG3	ENST00000194900.8 linkuse as main transcript	c.128G>T	p.Gly43Val	missense_variant	1/21	5		P1
DLG3	ENST00000463252.5 linkuse as main transcript	n.194G>T		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes

AF:

0.0000176

AC:

AN:

113419

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35573

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000667

AC:

AN:

104956

Hom.:

AF XY:

0.00

AC XY:

AN XY:

36114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000826

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:

0.0000199

AC:

AN:

1054004

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

343614

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000399

Gnomad4 SAS exome

AF:

0.0000798

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000608

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000176

AC:

AN:

113468

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35632

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.0000388

AC:

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

Mar 30, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.128G>T (p.G43V) alteration is located in exon 1 (coding exon 1) of the DLG3 gene. This alteration results from a G to T substitution at nucleotide position 128, causing the glycine (G) at amino acid position 43 to be replaced by a valine (V). The alteration has been observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the DLG3 c.128G>T alteration was observed in 0.007% (7/104956) of total alleles studied, with a frequency of 0.08% (7/8476) in the East Asian subpopulation; no hemizygous males were observed. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was reported to be maternally inherited a hemizygous Chinese male with global developmental delay, including speech delay, and craniofacial findings (Huifang, 2016). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.G43 amino acid is conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.G43V alteration is predicted to be tolerated by in silico analysis. 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

0.083

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.66

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.046

T;T

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.0098

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0040

D;D

Sift4G

Benign

0.24

T;T

Polyphen

1.0

.;D

Vest4

0.34

MutPred

0.31

Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);

MVP

0.38

MPC

0.93

ClinPred

0.16

GERP RS

1.8

Varity_R

0.12

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over