NM_000016.6:c.817_829delGCAATGGGAGCTT

Variant names:

• chr1-75749524-GTTGCAATGGGAGC-G
• rs875989872
• NM_000016.6:c.817_829delGCAATGGGAGCTT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000016.6(ACADM):​c.817_829delGCAATGGGAGCTT​(p.Ala273LeufsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACADM NM_000016.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.76
• Publications: 1 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-75749524-GTTGCAATGGGAGC-G is Pathogenic according to our data. Variant chr1-75749524-GTTGCAATGGGAGC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 226099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.817_829delGCAATGGGAGCTT	p.Ala273LeufsTer7	frameshift	Exon 9 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.916_928delGCAATGGGAGCTT	p.Ala306LeufsTer7	frameshift	Exon 10 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.829_841delGCAATGGGAGCTT	p.Ala277LeufsTer7	frameshift	Exon 9 of 12	NP_001120800.1	P11310-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.817_829delGCAATGGGAGCTT	p.Ala273LeufsTer7	frameshift	Exon 9 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.916_928delGCAATGGGAGCTT	p.Ala306LeufsTer7	frameshift	Exon 10 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.829_841delGCAATGGGAGCTT	p.Ala277LeufsTer7	frameshift	Exon 9 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461800 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs875989872; hg19: chr1-76215209;