1-75724646-C-G

Variant names:

• chr1-75724646-C-G
• rs61124994
• ENST00000541113.6:c.-142C>G

Variant summary

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

The ENST00000541113.6(ACADM):​c.-142C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 876,744 control chromosomes in the GnomAD database, including 479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (188 hom., cov: 32)
  • Exomes 𝑓: 0.025 (291 hom.)
• Consequence: ACADM ENST00000541113.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.14
• Publications: 0 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ENSG00000293044 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-75724646-C-G is Benign according to our data. Variant chr1-75724646-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 298065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000541113.6. 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.-142C>G		upstream_gene	N/A	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.-142C>G		upstream_gene	N/A	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.-142C>G		upstream_gene	N/A	NP_001120800.1	P11310-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000541113.6	TSL:1	c.-142C>G		5_prime_UTR	Exon 1 of 11	ENSP00000442324.2	F6YB23
	ACADM	ENST00000927351.1		c.-142C>G		5_prime_UTR	Exon 1 of 12	ENSP00000597410.1
	ACADM	ENST00000956292.1		c.-142C>G		5_prime_UTR	Exon 1 of 12	ENSP00000626351.1

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6487 AN: 152158 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0364

GnomAD4 exome AF: 0.0253 AC: 18299 AN: 724470 Hom.: 291 Cov.: 10 AF XY: 0.0245 AC XY: 8996 AN XY: 367104

African (AFR) AF: 0.0831 AC: 1191 AN: 14324

American (AMR) AF: 0.0265 AC: 344 AN: 12980

Ashkenazi Jewish (ASJ) AF: 0.00397 AC: 57 AN: 14342

East Asian (EAS) AF: 0.00 AC: 0 AN: 26024

South Asian (SAS) AF: 0.00750 AC: 347 AN: 46296

European-Finnish (FIN) AF: 0.0190 AC: 762 AN: 40178

Middle Eastern (MID) AF: 0.00631 AC: 19 AN: 3012

European-Non Finnish (NFE) AF: 0.0275 AC: 14708 AN: 533920

Other (OTH) AF: 0.0261 AC: 871 AN: 33394

GnomAD4 genome AF: 0.0426 AC: 6491 AN: 152274 Hom.: 188 Cov.: 32 AF XY: 0.0413 AC XY: 3076 AN XY: 74476

African (AFR) AF: 0.0864 AC: 3589 AN: 41552

American (AMR) AF: 0.0331 AC: 506 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4826

European-Finnish (FIN) AF: 0.0236 AC: 251 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0295 AC: 2008 AN: 68000

Other (OTH) AF: 0.0360 AC: 76 AN: 2112

Alfa AF: 0.0374 Hom.: 18

Bravo AF: 0.0454

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.61
PhyloP100		-1.1
PromoterAI		-0.34	Neutral
Mutation Taster		=300/0	polymorphism

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: rs61124994; hg19: chr1-76190331;