rs74090726

Variant names:

• chr1-75733592-A-C
• rs74090726
• NM_000016.6:c.351A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-75733592-A-C
• chr1-75733592-A-G
• chr1-75733592-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000016.6(ACADM):​c.351A>C​(p.Thr117Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,613,988 control chromosomes in the GnomAD database, including 1,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (276 hom., cov: 33)
  • Exomes 𝑓: 0.029 (865 hom.)
• Consequence: ACADM NM_000016.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.388
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-75733592-A-C is Benign according to our data. Variant chr1-75733592-A-C is described in ClinVar as Benign. ClinVar VariationId is 92263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.351A>C	p.Thr117Thr	synonymous	Exon 5 of 12	NP_000007.1
	ACADM	NM_001286043.2		c.450A>C	p.Thr150Thr	synonymous	Exon 6 of 13	NP_001272972.1
	ACADM	NM_001127328.3		c.363A>C	p.Thr121Thr	synonymous	Exon 5 of 12	NP_001120800.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.351A>C	p.Thr117Thr	synonymous	Exon 5 of 12	ENSP00000359878.5
	ACADM	ENST00000370834.9	TSL:1	c.450A>C	p.Thr150Thr	synonymous	Exon 6 of 13	ENSP00000359871.5
	ACADM	ENST00000420607.6	TSL:1	c.363A>C	p.Thr121Thr	synonymous	Exon 5 of 12	ENSP00000409612.2

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7442 AN: 152150 Hom.: 274 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.0269 AC: 6760 AN: 251442 AF XY: 0.0250

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0293 AC: 42870 AN: 1461720 Hom.: 865 Cov.: 31 AF XY: 0.0284 AC XY: 20637 AN XY: 727168

African (AFR) AF: 0.112 AC: 3763 AN: 33472

American (AMR) AF: 0.0256 AC: 1143 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 114 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39672

South Asian (SAS) AF: 0.00808 AC: 697 AN: 86258

European-Finnish (FIN) AF: 0.0197 AC: 1053 AN: 53418

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5766

European-Non Finnish (NFE) AF: 0.0308 AC: 34292 AN: 1111896

Other (OTH) AF: 0.0292 AC: 1761 AN: 60384

GnomAD4 genome AF: 0.0490 AC: 7458 AN: 152268 Hom.: 276 Cov.: 33 AF XY: 0.0474 AC XY: 3526 AN XY: 74450

African (AFR) AF: 0.108 AC: 4504 AN: 41532

American (AMR) AF: 0.0352 AC: 539 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4826

European-Finnish (FIN) AF: 0.0237 AC: 252 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2018 AN: 68028

Other (OTH) AF: 0.0393 AC: 83 AN: 2110

Alfa AF: 0.0332 Hom.: 407

Bravo AF: 0.0527

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0268

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Medium-chain acyl-coenzyme A dehydrogenase deficiency (6)
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	-	MCAD DEFICIENCY, MODIFIER OF (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.1
DANN	Benign	0.71
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs74090726; hg19: chr1-76199277; COSMIC: COSV107480042; COSMIC: COSV107480042;