chr1-75761289-T-TG

Position:

• chr1-75761289-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000016.6(ACADM):​c.1114dup​(p.Ala372GlyfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000012 (0 hom.)
• Consequence: ACADM NM_000016.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.21

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-75761289-T-TG is Pathogenic according to our data. Variant chr1-75761289-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 370160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.1114dup	p.Ala372GlyfsTer11	frameshift_variant	11/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.1114dup	p.Ala372GlyfsTer11	frameshift_variant	11/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251254 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 23, 2023	This variant is also known as c.1114–1115insG. This premature translational stop signal has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 23028790). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ala372Glyfs*11) in the ACADM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). ClinVar contains an entry for this variant (Variation ID: 370160). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: The ACADM c.1114dupG (p.Ala372Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent ACADM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP). The variant of interest was reported in one affected newborn via publications. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057516278; hg19: chr1-76226974;