1-75761337-A-G

Variant names:

• chr1-75761337-A-G
• rs1061337
• NM_000016.6:c.1161A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000016.6(ACADM):​c.1161A>G​(p.Val387Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,518 control chromosomes in the GnomAD database, including 62,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V387V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (4582 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57622 hom.)
• Consequence: ACADM NM_000016.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.28
• Publications: 30 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-75761337-A-G is Benign according to our data. Variant chr1-75761337-A-G is described in ClinVar as Benign. ClinVar VariationId is 92254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

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.1161A>G	p.Val387Val	synonymous	Exon 11 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.1260A>G	p.Val420Val	synonymous	Exon 12 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.1173A>G	p.Val391Val	synonymous	Exon 11 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.1161A>G	p.Val387Val	synonymous	Exon 11 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.1260A>G	p.Val420Val	synonymous	Exon 12 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.1173A>G	p.Val391Val	synonymous	Exon 11 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35826 AN: 152028 Hom.: 4582 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.242

GnomAD2 exomes AF: 0.234 AC: 58625 AN: 250748 AF XY: 0.236

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.0254

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.274 AC: 400907 AN: 1461372 Hom.: 57622 Cov.: 34 AF XY: 0.272 AC XY: 197437 AN XY: 727024

African (AFR) AF: 0.150 AC: 5020 AN: 33472

American (AMR) AF: 0.218 AC: 9768 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5399 AN: 26126

East Asian (EAS) AF: 0.0299 AC: 1187 AN: 39688

South Asian (SAS) AF: 0.184 AC: 15863 AN: 86248

European-Finnish (FIN) AF: 0.256 AC: 13682 AN: 53360

Middle Eastern (MID) AF: 0.244 AC: 1406 AN: 5766

European-Non Finnish (NFE) AF: 0.300 AC: 333020 AN: 1111614

Other (OTH) AF: 0.258 AC: 15562 AN: 60376

GnomAD4 genome AF: 0.236 AC: 35835 AN: 152146 Hom.: 4582 Cov.: 32 AF XY: 0.232 AC XY: 17278 AN XY: 74378

African (AFR) AF: 0.148 AC: 6144 AN: 41530

American (AMR) AF: 0.254 AC: 3880 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 714 AN: 3470

East Asian (EAS) AF: 0.0336 AC: 174 AN: 5174

South Asian (SAS) AF: 0.188 AC: 907 AN: 4822

European-Finnish (FIN) AF: 0.257 AC: 2716 AN: 10576

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.301 AC: 20430 AN: 67972

Other (OTH) AF: 0.241 AC: 511 AN: 2116

Alfa AF: 0.273 Hom.: 20191

Bravo AF: 0.230

Asia WGS AF: 0.163 AC: 568 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.297

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Medium-chain acyl-coenzyme A dehydrogenase deficiency (5)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.3
DANN	Benign	0.67
PhyloP100		1.3
Mutation Taster		=98/2	polymorphism (auto)

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: rs1061337; hg19: chr1-76227022; COSMIC: COSV63720150; COSMIC: COSV63720150;