1-75739958-C-A

Variant names:

• chr1-75739958-C-A
• rs12127402
• NM_000016.6:c.469-22C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000016.6(ACADM):​c.469-22C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,560,800 control chromosomes in the GnomAD database, including 62,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5020 hom., cov: 33)
  • Exomes 𝑓: 0.28 (57511 hom.)
• Consequence: ACADM NM_000016.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.227
• Publications: 6 publications found

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]

ACADM Gene-Disease associations (from GenCC):

• medium chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-75739958-C-A is Benign according to our data. Variant chr1-75739958-C-A is described in ClinVar as Benign. ClinVar VariationId is 254690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.469-22C>A		intron_variant	Intron 6 of 11	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.469-22C>A		intron_variant	Intron 6 of 11	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37812 AN: 151968 Hom.: 5022 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.247 AC: 55471 AN: 224930 AF XY: 0.246

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.284

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.0257

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.279 AC: 393519 AN: 1408716 Hom.: 57511 Cov.: 25 AF XY: 0.277 AC XY: 193381 AN XY: 699142

African (AFR) AF: 0.172 AC: 5489 AN: 31940

American (AMR) AF: 0.285 AC: 11368 AN: 39820

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 5274 AN: 24954

East Asian (EAS) AF: 0.0301 AC: 1166 AN: 38776

South Asian (SAS) AF: 0.187 AC: 14575 AN: 77768

European-Finnish (FIN) AF: 0.262 AC: 13530 AN: 51706

Middle Eastern (MID) AF: 0.246 AC: 1369 AN: 5566

European-Non Finnish (NFE) AF: 0.301 AC: 325442 AN: 1079966

Other (OTH) AF: 0.263 AC: 15306 AN: 58220

GnomAD4 genome AF: 0.249 AC: 37828 AN: 152084 Hom.: 5020 Cov.: 33 AF XY: 0.245 AC XY: 18241 AN XY: 74342

African (AFR) AF: 0.172 AC: 7137 AN: 41490

American (AMR) AF: 0.291 AC: 4442 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3470

East Asian (EAS) AF: 0.0349 AC: 181 AN: 5184

South Asian (SAS) AF: 0.193 AC: 932 AN: 4820

European-Finnish (FIN) AF: 0.263 AC: 2775 AN: 10548

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20735 AN: 67984

Other (OTH) AF: 0.253 AC: 534 AN: 2108

Alfa AF: 0.259 Hom.: 982

Bravo AF: 0.246

Asia WGS AF: 0.170 AC: 589 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 08, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.46
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12127402; hg19: chr1-76205643;