rs2230178

Variant names:

• chr17-7220187-G-A
• rs2230178
• NM_000018.4:c.128G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BP2

This summary comes from the ClinGen Evidence Repository: The c.128G>A variant in ACADVL is well characterized as a benign polymorphism, being present in several VLCAD cases with alternate pathogenic variants (BP2; PMIDs: 11914034, 15210884, more in literature). The highest population minor allele frequency in gnomAD v2.1.1 is 0.17 in the East Asian 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 0.259, 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 criteria to be classified as benign for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: BA1; BP2; BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA341517/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.029 (144 hom., cov: 33)
  • Exomes 𝑓: 0.014 (868 hom.)
• Consequence: ACADVL NM_001270448.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 0.732
• Publications: 19 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 -10 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• 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_001270448.2. 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
	ACADVL	NM_000018.4	MANE Select	c.128G>A	p.Gly43Asp	missense	Exon 2 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270448.2		c.-101G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	NP_001257377.1	B3KPA6
	ACADVL	NM_001270447.2		c.197G>A	p.Gly66Asp	missense	Exon 3 of 21	NP_001257376.1	P49748-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.128G>A	p.Gly43Asp	missense	Exon 2 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.128G>A	p.Gly43Asp	missense	Exon 2 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.197G>A	p.Gly66Asp	missense	Exon 3 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4450 AN: 152190 Hom.: 143 Cov.: 33

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0418

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0361 AC: 4696 AN: 129906 AF XY: 0.0334

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.0561

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.171

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0143 AC: 19801 AN: 1381352 Hom.: 868 Cov.: 35 AF XY: 0.0143 AC XY: 9762 AN XY: 681450

African (AFR) AF: 0.0464 AC: 1476 AN: 31792

American (AMR) AF: 0.0548 AC: 1940 AN: 35418

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 949 AN: 24998

East Asian (EAS) AF: 0.189 AC: 6789 AN: 35988

South Asian (SAS) AF: 0.0202 AC: 1598 AN: 79104

European-Finnish (FIN) AF: 0.0208 AC: 703 AN: 33836

Middle Eastern (MID) AF: 0.0261 AC: 115 AN: 4404

European-Non Finnish (NFE) AF: 0.00443 AC: 4780 AN: 1078152

Other (OTH) AF: 0.0252 AC: 1451 AN: 57660

GnomAD4 genome AF: 0.0293 AC: 4459 AN: 152308 Hom.: 144 Cov.: 33 AF XY: 0.0316 AC XY: 2350 AN XY: 74478

African (AFR) AF: 0.0458 AC: 1906 AN: 41572

American (AMR) AF: 0.0421 AC: 644 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3470

East Asian (EAS) AF: 0.168 AC: 870 AN: 5176

South Asian (SAS) AF: 0.0300 AC: 145 AN: 4828

European-Finnish (FIN) AF: 0.0260 AC: 276 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00610 AC: 415 AN: 68006

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0241 Hom.: 48

Bravo AF: 0.0336

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0266 AC: 74

ESP6500EA AF: 0.00452 AC: 28

ExAC AF: 0.0189 AC: 1238

Asia WGS AF: 0.0950 AC: 330 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	Very long chain acyl-CoA dehydrogenase deficiency (7)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.73
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.26
Sift	Benign	0.35	T
Sift4G	Benign	0.10	T
Polyphen		0.041	B
Vest4		0.094
MPC		0.39
ClinPred		0.0030	T
GERP RS		0.59
PromoterAI		-0.097	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.043
gMVP		0.31
Mutation Taster		=99/1	polymorphism (auto)

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: rs2230178; hg19: chr17-7123506; COSMIC: COSV57238038; COSMIC: COSV57238038;