17-7217740-T-TAGAAGC

Variant names:

• chr17-7217740-T-TAGAAGC
• rs1555526655
• NM_001365.5:c.159+495_159+500dupGCTTCT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001270447.2(ACADVL):​c.61_66dupGAAGCA​(p.Glu21_Ala22dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000013 in 1,533,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ACADVL NM_001270447.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.168
• Publications: 0 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001270447.2.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270447.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG4	NM_001365.5	MANE Plus Clinical	c.159+495_159+500dupGCTTCT		intron	N/A	NP_001356.1	P78352-2
	ACADVL	NM_001270447.2		c.61_66dupGAAGCA	p.Glu21_Ala22dup	conservative_inframe_insertion	Exon 2 of 21	NP_001257376.1	P49748-3
	DLG4	NM_001321074.1		c.159+495_159+500dupGCTTCT		intron	N/A	NP_001308003.1	B9EGL1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG4	ENST00000648172.9	MANE Plus Clinical	c.159+495_159+500dupGCTTCT		intron	N/A	ENSP00000497806.3	P78352-2
	DLG4	ENST00000399510.8	TSL:1	c.159+495_159+500dupGCTTCT		intron	N/A	ENSP00000382428.3	B9EGL1
	DLG4	ENST00000491753.2	TSL:2	n.159+495_159+500dupGCTTCT		intron	N/A	ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151196 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000244

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1382116 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 682026

African (AFR) AF: 0.0000317 AC: 1 AN: 31566

American (AMR) AF: 0.00 AC: 0 AN: 35644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 35668

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078064

Other (OTH) AF: 0.00 AC: 0 AN: 57808

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151196 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73800

African (AFR) AF: 0.0000244 AC: 1 AN: 41040

American (AMR) AF: 0.00 AC: 0 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67836

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Very long chain acyl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=84/16	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1555526655; hg19: chr17-7121059;