rs759282824

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The NM_001365.5(DLG4):c.20-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000641 in 1,559,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

DLG4
NM_001365.5 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 3.61

Variant links:

Genes affected

DLG4 (HGNC:2903): (discs large MAGUK scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DLG4 links:

ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04296875 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.3, offset of 7, new splice context is: tgcatctcactacctcccAGgtc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
DLG4	NM_001365.5 link	c.20-1G>C	splice_acceptor_variant, intron_variant	Intron 1 of 21	NP_001356.1	P78352-2B7Z647B9EGL1
DLG4	NM_001321074.1 link	c.20-1G>C	splice_acceptor_variant, intron_variant	Intron 1 of 21	NP_001308003.1	B9EGL1
ACADVL	NM_001270447.2 link	c.131+822C>G	intron_variant	Intron 2 of 20	NP_001257376.1	P49748-3
DLG4	NR_135527.1 link	n.1221-1G>C	splice_acceptor_variant, intron_variant	Intron 1 of 20

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
DLG4	ENST00000648172.8 link	c.20-1G>C	splice_acceptor_variant, intron_variant	Intron 1 of 21		ENSP00000497806.3	P78352-2
DLG4	ENST00000399510.8 link	c.20-1G>C	splice_acceptor_variant, intron_variant	Intron 1 of 21	1	ENSP00000382428.3	B9EGL1
DLG4	ENST00000491753.2 link	n.20-1G>C	splice_acceptor_variant, intron_variant	Intron 1 of 20	2	ENSP00000467897.2	B7Z3U2
ACADVL	ENST00000543245.6 link	c.131+822C>G	intron_variant	Intron 2 of 20	2	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000605

AC:

AN:

165310

Hom.:

AF XY:

0.00

AC XY:

AN XY:

87796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1407468

Hom.:

Cov.:

AF XY:

0.00000432

AC XY:

AN XY:

695016

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000831

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000854

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This region of the gene is excluded from other biologically relevant transcripts Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autism spectrum disorder

Other:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.78

GERP RS

5.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

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