rs76547988

Positions:

• chr17-7221965-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000018.4(ACADVL):​c.636C>T​(p.Ala212Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,088 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (10 hom.)
• Consequence: ACADVL NM_000018.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: -7.07

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]

ACADVL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-7221965-C-T is Benign according to our data. Variant chr17-7221965-C-T is described in ClinVar as [Benign]. Clinvar id is 324988.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-7.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00521 (793/152228) while in subpopulation AFR AF= 0.0179 (743/41528). AF 95% confidence interval is 0.0168. There are 6 homozygotes in gnomad4. There are 370 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.636C>T	p.Ala212Ala	synonymous_variant	8/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.636C>T	p.Ala212Ala	synonymous_variant	8/20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 795 AN: 152110 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00144 AC: 361 AN: 251296 Hom.: 3 AF XY: 0.00119 AC XY: 161 AN XY: 135862

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000640 AC: 936 AN: 1461860 Hom.: 10 Cov.: 32 AF XY: 0.000606 AC XY: 441 AN XY: 727236

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00521 AC: 793 AN: 152228 Hom.: 6 Cov.: 32 AF XY: 0.00497 AC XY: 370 AN XY: 74424

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00241 Hom.: 1

Bravo AF: 0.00576

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Benign:5

Benign, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Mar 06, 2022	The c.636C>T (p.Ala212=) variant is a synonymous (silent) variant that is not predicted by Splice AI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD 3.1.2 is 0.01799 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1. To our knowledge, this variant is not in the literature in a proband with VLCAD or ACADVL associated disease or in functional studies. 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, BP7. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2017	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.3
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs76547988; hg19: chr17-7125284;