rs181322317

Positions:

• chr1-75739971-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000016.6(ACADM):​c.469-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,588,988 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: ACADM NM_000016.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001907
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0250

Genes affected

ACADM (HGNC:89): (acyl-CoA dehydrogenase medium chain) This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-75739971-A-G is Benign according to our data. Variant chr1-75739971-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226107.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.469-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.469-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152236 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000585 AC: 138 AN: 235704 Hom.: 1 AF XY: 0.000456 AC XY: 58 AN XY: 127326

Gnomad AFR exome AF: 0.00777

Gnomad AMR exome AF: 0.000448

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000377

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000237 AC: 341 AN: 1436634 Hom.: 3 Cov.: 29 AF XY: 0.000213 AC XY: 152 AN XY: 713696

Gnomad4 AFR exome AF: 0.00801

Gnomad4 AMR exome AF: 0.000557

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000748

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000909

Gnomad4 OTH exome AF: 0.000690

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152354 Hom.: 2 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74512

Gnomad4 AFR AF: 0.00697

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2015	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2018	Variant summary: ACADM c.469-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00074 in 262480 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0074 in the gnomAD database. The observed variant frequency within African control individuals is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency phenotype (0.0054), suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.469-9A>G in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.0
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs181322317; hg19: chr1-76205656; COSMIC: COSV57714726; COSMIC: COSV57714726;