NM_000016.6:c.31-37C>T

Variant names:

• chr1-75728364-C-T
• rs201590881
• NM_000016.6:c.31-37C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000016.6(ACADM):​c.31-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,537,152 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: ACADM NM_000016.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.582
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-75728364-C-T is Benign according to our data. Variant chr1-75728364-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000016.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.31-37C>T		intron	N/A	NP_000007.1
	ACADM	NM_001286043.2		c.31-37C>T		intron	N/A	NP_001272972.1
	ACADM	NM_001127328.3		c.31-25C>T		intron	N/A	NP_001120800.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.31-37C>T		intron	N/A	ENSP00000359878.5
	ACADM	ENST00000370834.9	TSL:1	c.31-37C>T		intron	N/A	ENSP00000359871.5
	ACADM	ENST00000420607.6	TSL:1	c.31-25C>T		intron	N/A	ENSP00000409612.2

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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

GnomAD2 exomes AF: 0.000572 AC: 141 AN: 246582 AF XY: 0.000442

Gnomad AFR exome AF: 0.00762

Gnomad AMR exome AF: 0.000412

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000237 AC: 328 AN: 1384888 Hom.: 2 Cov.: 21 AF XY: 0.000209 AC XY: 145 AN XY: 693322

African (AFR) AF: 0.00785 AC: 248 AN: 31610

American (AMR) AF: 0.000546 AC: 24 AN: 43916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25432

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.0000719 AC: 6 AN: 83404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.00000956 AC: 10 AN: 1045694

Other (OTH) AF: 0.000692 AC: 40 AN: 57818

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74442

African (AFR) AF: 0.00703 AC: 292 AN: 41552

American (AMR) AF: 0.000916 AC: 14 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jun 17, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 20, 2015

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.88
DANN	Benign	0.65
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism

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: rs201590881; hg19: chr1-76194049;