1-75732751-T-C

Variant names:

• chr1-75732751-T-C
• rs2275378
• NM_000016.6:c.216+10T>C

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.216+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,609,978 control chromosomes in the GnomAD database, including 80,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7012 hom., cov: 33)
  • Exomes 𝑓: 0.31 (73037 hom.)
• Consequence: ACADM NM_000016.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.00800
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-75732751-T-C is Benign according to our data. Variant chr1-75732751-T-C is described in ClinVar as Benign. ClinVar VariationId is 92259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 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.216+10T>C		intron	N/A	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.216+10T>C		intron	N/A	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.228+10T>C		intron	N/A	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.216+10T>C		intron	N/A	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.216+10T>C		intron	N/A	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.228+10T>C		intron	N/A	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45515 AN: 152008 Hom.: 7008 Cov.: 33

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0352

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.295

GnomAD2 exomes AF: 0.276 AC: 69280 AN: 251044 AF XY: 0.273

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.0260

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.310 AC: 452413 AN: 1457852 Hom.: 73037 Cov.: 30 AF XY: 0.306 AC XY: 222146 AN XY: 725560

African (AFR) AF: 0.295 AC: 9836 AN: 33396

American (AMR) AF: 0.312 AC: 13948 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5640 AN: 26116

East Asian (EAS) AF: 0.0303 AC: 1203 AN: 39640

South Asian (SAS) AF: 0.197 AC: 17016 AN: 86184

European-Finnish (FIN) AF: 0.282 AC: 15037 AN: 53414

Middle Eastern (MID) AF: 0.254 AC: 1464 AN: 5754

European-Non Finnish (NFE) AF: 0.334 AC: 370549 AN: 1108376

Other (OTH) AF: 0.294 AC: 17720 AN: 60260

GnomAD4 genome AF: 0.299 AC: 45550 AN: 152126 Hom.: 7012 Cov.: 33 AF XY: 0.294 AC XY: 21896 AN XY: 74358

African (AFR) AF: 0.287 AC: 11919 AN: 41494

American (AMR) AF: 0.327 AC: 4995 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3472

East Asian (EAS) AF: 0.0347 AC: 180 AN: 5192

South Asian (SAS) AF: 0.200 AC: 965 AN: 4814

European-Finnish (FIN) AF: 0.285 AC: 3017 AN: 10568

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22734 AN: 67976

Other (OTH) AF: 0.295 AC: 624 AN: 2114

Alfa AF: 0.306 Hom.: 2383

Bravo AF: 0.302

Asia WGS AF: 0.182 AC: 633 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Medium-chain acyl-coenzyme A dehydrogenase deficiency (5)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		-0.0080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2275378; hg19: chr1-76198436;