rs34153370

Variant names:

• chr17-7220127-G-A
• rs34153370
• NM_000018.4:c.68G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7220127-G-A
• chr17-7220127-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.68G>A variant in ACADVL is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid 23 (p.Arg23Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01223 in the Latino population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.123, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (VCEP specifications v2.0, approved on 09/16/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA341524/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (8 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.460
• Publications: 3 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder 62

  Inheritance: AD Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000018.4. 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
	ACADVL	NM_000018.4	MANE Select	c.68G>A	p.Arg23Gln	missense	Exon 2 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.137G>A	p.Arg46Gln	missense	Exon 3 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.68G>A	p.Arg23Gln	missense	Exon 2 of 19	NP_001029031.1	P49748-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.68G>A	p.Arg23Gln	missense	Exon 2 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.68G>A	p.Arg23Gln	missense	Exon 2 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.137G>A	p.Arg46Gln	missense	Exon 3 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

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: 0.000955

GnomAD2 exomes AF: 0.00200 AC: 335 AN: 167218 AF XY: 0.00135

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000292 AC: 413 AN: 1413968 Hom.: 8 Cov.: 35 AF XY: 0.000223 AC XY: 156 AN XY: 700272

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.0105 AC: 401 AN: 38338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 38590

South Asian (SAS) AF: 0.00 AC: 0 AN: 82134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5352

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095858

Other (OTH) AF: 0.000186 AC: 11 AN: 59070

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00372 AC: 57 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000858

ExAC AF: 0.00110 AC: 123

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Very long chain acyl-CoA dehydrogenase deficiency (6)
-	-	2	not provided (2)
-	-	1	ACADVL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0042	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.46
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.12
Sift	Benign	0.038	D
Sift4G	Benign	0.38	T
Polyphen		0.0060	B
Vest4		0.25
MVP		0.87
MPC		0.23
ClinPred		0.036	T
GERP RS		2.7
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
Varity_R		0.076
gMVP		0.15
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs34153370; hg19: chr17-7123446;