1-75745884-A-G

Variant names:

• chr1-75745884-A-G
• rs2229249
• NM_000016.6:c.678A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000016.6(ACADM):​c.678A>G​(p.Ala226Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000888 in 1,613,438 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (24 hom.)
• Consequence: ACADM NM_000016.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.165
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-75745884-A-G is Benign according to our data. Variant chr1-75745884-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000857 (1252/1461100) while in subpopulation AMR AF = 0.0269 (1204/44724). AF 95% confidence interval is 0.0257. There are 24 homozygotes in GnomAdExome4. There are 544 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.678A>G	p.Ala226Ala	synonymous	Exon 8 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.777A>G	p.Ala259Ala	synonymous	Exon 9 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.690A>G	p.Ala230Ala	synonymous	Exon 8 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.678A>G	p.Ala226Ala	synonymous	Exon 8 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.777A>G	p.Ala259Ala	synonymous	Exon 9 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.690A>G	p.Ala230Ala	synonymous	Exon 8 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152220 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

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: 0.000956

GnomAD2 exomes AF: 0.00423 AC: 1064 AN: 251324 AF XY: 0.00332

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.0302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000857 AC: 1252 AN: 1461100 Hom.: 24 Cov.: 30 AF XY: 0.000748 AC XY: 544 AN XY: 726922

African (AFR) AF: 0.000179 AC: 6 AN: 33468

American (AMR) AF: 0.0269 AC: 1204 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111410

Other (OTH) AF: 0.000547 AC: 33 AN: 60366

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152338 Hom.: 4 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74496

African (AFR) AF: 0.000217 AC: 9 AN: 41564

American (AMR) AF: 0.0110 AC: 169 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00131 Hom.: 2

Bravo AF: 0.00248

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Medium-chain acyl-coenzyme A dehydrogenase deficiency (4)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	ACADM-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.2
DANN	Benign	0.81
PhyloP100		-0.17
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2229249; hg19: chr1-76211569; COSMIC: COSV100273521; COSMIC: COSV100273521;