1-75724754-T-C

Variant names:

• chr1-75724754-T-C
• rs59932454
• ENST00000526196.5:n.-34T>C

Variant summary

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

The ENST00000526196.5(ACADM):​n.-34T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,535,728 control chromosomes in the GnomAD database, including 1,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (278 hom., cov: 32)
  • Exomes 𝑓: 0.029 (808 hom.)
• Consequence: ACADM ENST00000526196.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.21
• Publications: 3 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

ENSG00000293044 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-75724754-T-C is Benign according to our data. Variant chr1-75724754-T-C is described in ClinVar as Benign. ClinVar VariationId is 136258.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: ENST00000526196.5. 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.-34T>C		5_prime_UTR	Exon 1 of 12	NP_000007.1
	ACADM	NM_001286043.2		c.-34T>C		5_prime_UTR	Exon 1 of 13	NP_001272972.1
	ACADM	NM_001127328.3		c.-34T>C		5_prime_UTR	Exon 1 of 12	NP_001120800.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000526196.5	TSL:1	n.-34T>C		non_coding_transcript_exon	Exon 1 of 11	ENSP00000431953.1
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.-34T>C		5_prime_UTR	Exon 1 of 12	ENSP00000359878.5
	ACADM	ENST00000370834.9	TSL:1	c.-34T>C		5_prime_UTR	Exon 1 of 13	ENSP00000359871.5

Frequencies

GnomAD3 genomes AF: 0.0490 AC: 7455 AN: 152110 Hom.: 276 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0401

GnomAD2 exomes AF: 0.0258 AC: 4923 AN: 190664 AF XY: 0.0240

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.00416

Gnomad EAS exome AF: 0.0000885

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0275

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0292 AC: 40330 AN: 1383500 Hom.: 808 Cov.: 30 AF XY: 0.0282 AC XY: 19359 AN XY: 685884

African (AFR) AF: 0.112 AC: 3232 AN: 28776

American (AMR) AF: 0.0240 AC: 839 AN: 35018

Ashkenazi Jewish (ASJ) AF: 0.00412 AC: 96 AN: 23324

East Asian (EAS) AF: 0.00 AC: 0 AN: 33110

South Asian (SAS) AF: 0.00783 AC: 605 AN: 77224

European-Finnish (FIN) AF: 0.0193 AC: 1001 AN: 51784

Middle Eastern (MID) AF: 0.00801 AC: 44 AN: 5496

European-Non Finnish (NFE) AF: 0.0307 AC: 32876 AN: 1072066

Other (OTH) AF: 0.0289 AC: 1637 AN: 56702

GnomAD4 genome AF: 0.0491 AC: 7471 AN: 152228 Hom.: 278 Cov.: 32 AF XY: 0.0475 AC XY: 3537 AN XY: 74436

African (AFR) AF: 0.109 AC: 4522 AN: 41536

American (AMR) AF: 0.0350 AC: 535 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4828

European-Finnish (FIN) AF: 0.0235 AC: 249 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0297 AC: 2019 AN: 68004

Other (OTH) AF: 0.0397 AC: 84 AN: 2116

Alfa AF: 0.0347 Hom.: 62

Bravo AF: 0.0528

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.47
PhyloP100		-2.2
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs59932454; hg19: chr1-76190439; COSMIC: COSV63720157; COSMIC: COSV63720157;