dbSNP rs1555526472: DLG4:c.-27C>T (chr17-7217174-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001321075.3(DLG4):c.-27C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000265 in 1,132,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Consequence

DLG4
NM_001321075.3 5_prime_UTR

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.35

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

very long chain acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3 link	c.-27C>T		5_prime_UTR_variant	Exon 1 of 20	ENST00000399506.9	NP_001308004.1	P78352-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLG4	ENST00000399506.9 link	c.-27C>T	5_prime_UTR_variant	Exon 1 of 20	2	NM_001321075.3	ENSP00000382425.2	P78352-1
DLG4	ENST00000647975.1 link	c.-27C>T	5_prime_UTR_variant	Exon 1 of 7			ENSP00000497912.1	A0A3B3ITI9
DLG4	ENST00000648172.9 link	c.159+1067C>T	intron_variant	Intron 3 of 21			ENSP00000497806.3	P78352-2
DLG4	ENST00000491753.2 link	n.159+1067C>T	intron_variant	Intron 3 of 20	2		ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000265

AC:

AN:

1132174

Hom.:

Cov.:

AF XY:

0.00000369

AC XY:

AN XY:

541526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23336

American (AMR)

AF:

0.00

AC:

AN:

9320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14976

East Asian (EAS)

AF:

0.00

AC:

AN:

27058

South Asian (SAS)

AF:

0.00

AC:

AN:

27474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3556

European-Non Finnish (NFE)

AF:

0.00000318

AC:

AN:

943112

Other (OTH)

AF:

0.00

AC:

AN:

45264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Uncertain:1

Mar 29, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Benign

0.65

PhyloP100

3.3

GERP RS

4.0

PromoterAI

0.072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

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

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rs1555526472

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over