1-75732751-T-C

Variant names:

• chr1-75732751-T-C
• rs2275378
• NM_000016.6:c.216+10T>C

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.216+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,609,978 control chromosomes in the GnomAD database, including 80,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7012 hom., cov: 33)
  • Exomes 𝑓: 0.31 (73037 hom.)
• Consequence: ACADM NM_000016.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.00800
• Publications: 19 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=-0.61).
• BP6: Variant 1-75732751-T-C is Benign according to our data. Variant chr1-75732751-T-C is described in ClinVar as Benign. ClinVar VariationId is 92259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.216+10T>C		intron_variant	Intron 3 of 11	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.216+10T>C		intron_variant	Intron 3 of 11	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45515 AN: 152008 Hom.: 7008 Cov.: 33

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0352

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.295

GnomAD2 exomes AF: 0.276 AC: 69280 AN: 251044 AF XY: 0.273

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.0260

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.310 AC: 452413 AN: 1457852 Hom.: 73037 Cov.: 30 AF XY: 0.306 AC XY: 222146 AN XY: 725560

African (AFR) AF: 0.295 AC: 9836 AN: 33396

American (AMR) AF: 0.312 AC: 13948 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5640 AN: 26116

East Asian (EAS) AF: 0.0303 AC: 1203 AN: 39640

South Asian (SAS) AF: 0.197 AC: 17016 AN: 86184

European-Finnish (FIN) AF: 0.282 AC: 15037 AN: 53414

Middle Eastern (MID) AF: 0.254 AC: 1464 AN: 5754

European-Non Finnish (NFE) AF: 0.334 AC: 370549 AN: 1108376

Other (OTH) AF: 0.294 AC: 17720 AN: 60260

GnomAD4 genome AF: 0.299 AC: 45550 AN: 152126 Hom.: 7012 Cov.: 33 AF XY: 0.294 AC XY: 21896 AN XY: 74358

African (AFR) AF: 0.287 AC: 11919 AN: 41494

American (AMR) AF: 0.327 AC: 4995 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3472

East Asian (EAS) AF: 0.0347 AC: 180 AN: 5192

South Asian (SAS) AF: 0.200 AC: 965 AN: 4814

European-Finnish (FIN) AF: 0.285 AC: 3017 AN: 10568

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22734 AN: 67976

Other (OTH) AF: 0.295 AC: 624 AN: 2114

Alfa AF: 0.306 Hom.: 2383

Bravo AF: 0.302

Asia WGS AF: 0.182 AC: 633 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Benign:5

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 08, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

not specified Benign:3

Sep 14, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		-0.0080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2275378; hg19: chr1-76198436;