rs2017365

Variant names:

• chr17-7219305-G-A
• rs2017365
• ENST00000491753.2:n.-456C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000491753.2(DLG4):​n.-456C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 757,688 control chromosomes in the GnomAD database, including 139,323 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (24134 hom., cov: 31)
  • Exomes 𝑓: 0.61 (115189 hom.)
• Consequence: DLG4 ENST00000491753.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430
• Publications: 26 publications found

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]

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NR_135527.1	n.746C>T		non_coding_transcript_exon_variant	Exon 1 of 21
DLG4	NM_001365.5	c.-456C>T		5_prime_UTR_variant	Exon 1 of 22		NP_001356.1
DLG4	NM_001321074.1	c.-456C>T		5_prime_UTR_variant	Exon 1 of 22		NP_001308003.1
ACADVL	NM_001270447.2	c.132-817G>A		intron_variant	Intron 2 of 20		NP_001257376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000491753.2	n.-456C>T		non_coding_transcript_exon_variant	Exon 1 of 21	2		ENSP00000467897.2
DLG4	ENST00000648172.9	c.-456C>T		5_prime_UTR_variant	Exon 1 of 22			ENSP00000497806.3
DLG4	ENST00000491753.2	n.-456C>T		5_prime_UTR_variant	Exon 1 of 21	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83679 AN: 151780 Hom.: 24109 Cov.: 31

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.583

GnomAD4 exome AF: 0.613 AC: 371530 AN: 605790 Hom.: 115189 Cov.: 8 AF XY: 0.614 AC XY: 175814 AN XY: 286184

African (AFR) AF: 0.347 AC: 3793 AN: 10940

American (AMR) AF: 0.516 AC: 1847 AN: 3580

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2578 AN: 4372

East Asian (EAS) AF: 0.466 AC: 1894 AN: 4068

South Asian (SAS) AF: 0.648 AC: 11328 AN: 17484

European-Finnish (FIN) AF: 0.637 AC: 1081 AN: 1696

Middle Eastern (MID) AF: 0.722 AC: 921 AN: 1276

European-Non Finnish (NFE) AF: 0.620 AC: 335884 AN: 541764

Other (OTH) AF: 0.592 AC: 12204 AN: 20610

GnomAD4 genome AF: 0.551 AC: 83746 AN: 151898 Hom.: 24134 Cov.: 31 AF XY: 0.555 AC XY: 41214 AN XY: 74220

African (AFR) AF: 0.373 AC: 15463 AN: 41404

American (AMR) AF: 0.549 AC: 8389 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2035 AN: 3466

East Asian (EAS) AF: 0.483 AC: 2487 AN: 5154

South Asian (SAS) AF: 0.642 AC: 3085 AN: 4808

European-Finnish (FIN) AF: 0.675 AC: 7117 AN: 10548

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43140 AN: 67928

Other (OTH) AF: 0.588 AC: 1243 AN: 2114

Alfa AF: 0.617 Hom.: 33280

Bravo AF: 0.531

Asia WGS AF: 0.570 AC: 1986 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		0.043
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2017365; hg19: chr17-7122624;