chr17-7218466-T-C

Variant names:

• chr17-7218466-T-C
• rs2521985
• NM_001365.5:c.118+75A>G

Variant summary

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

The NM_001365.5(DLG4):​c.118+75A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,458,246 control chromosomes in the GnomAD database, including 307,608 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 0.69 (36639 hom., cov: 32)
  • Exomes 𝑓: 0.64 (270969 hom.)
• Consequence: DLG4 NM_001365.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 18 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001365.5	c.118+75A>G		intron_variant	Intron 2 of 21	ENST00000648172.9	NP_001356.1
DLG4	NM_001321074.1	c.118+75A>G		intron_variant	Intron 2 of 21		NP_001308003.1
ACADVL	NM_001270447.2	c.131+648T>C		intron_variant	Intron 2 of 20		NP_001257376.1
DLG4	NR_135527.1	n.1319+75A>G		intron_variant	Intron 2 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000648172.9	c.118+75A>G		intron_variant	Intron 2 of 21		NM_001365.5	ENSP00000497806.3
DLG4	ENST00000491753.2	n.118+75A>G		intron_variant	Intron 2 of 20	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104837 AN: 151922 Hom.: 36581 Cov.: 32

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.653

Gnomad SAS AF: 0.678

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.691

GnomAD4 exome AF: 0.642 AC: 839106 AN: 1306206 Hom.: 270969 Cov.: 21 AF XY: 0.644 AC XY: 417979 AN XY: 648950

African (AFR) AF: 0.805 AC: 23857 AN: 29636

American (AMR) AF: 0.584 AC: 20779 AN: 35562

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 15737 AN: 24578

East Asian (EAS) AF: 0.646 AC: 22803 AN: 35308

South Asian (SAS) AF: 0.679 AC: 52508 AN: 77276

European-Finnish (FIN) AF: 0.680 AC: 33081 AN: 48678

Middle Eastern (MID) AF: 0.749 AC: 4102 AN: 5474

European-Non Finnish (NFE) AF: 0.634 AC: 630473 AN: 994796

Other (OTH) AF: 0.651 AC: 35766 AN: 54898

GnomAD4 genome AF: 0.690 AC: 104957 AN: 152040 Hom.: 36639 Cov.: 32 AF XY: 0.692 AC XY: 51432 AN XY: 74316

African (AFR) AF: 0.794 AC: 32915 AN: 41476

American (AMR) AF: 0.636 AC: 9723 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2178 AN: 3464

East Asian (EAS) AF: 0.652 AC: 3357 AN: 5146

South Asian (SAS) AF: 0.680 AC: 3276 AN: 4820

European-Finnish (FIN) AF: 0.701 AC: 7420 AN: 10584

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43813 AN: 67942

Other (OTH) AF: 0.695 AC: 1468 AN: 2112

Alfa AF: 0.695 Hom.: 6143

Bravo AF: 0.689

Asia WGS AF: 0.693 AC: 2413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.5
DANN	Benign	0.56
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2521985; hg19: chr17-7121785; COSMIC: COSV57242211; COSMIC: COSV57242211;