1-75740000-T-G

Variant names:

• chr1-75740000-T-G
• rs78392995
• NM_000016.6:c.489T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001286043.2(ACADM):​c.588T>G​(p.Pro196Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,612,218 control chromosomes in the GnomAD database, including 217 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. P196P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (116 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (101 hom.)
• Consequence: ACADM NM_001286043.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.311
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-75740000-T-G is Benign according to our data. Variant chr1-75740000-T-G is described in ClinVar as Benign. ClinVar VariationId is 92266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.311 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286043.2. 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.489T>G	p.Pro163Pro	synonymous	Exon 7 of 12	NP_000007.1
	ACADM	NM_001286043.2		c.588T>G	p.Pro196Pro	synonymous	Exon 8 of 13	NP_001272972.1
	ACADM	NM_001127328.3		c.501T>G	p.Pro167Pro	synonymous	Exon 7 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.489T>G	p.Pro163Pro	synonymous	Exon 7 of 12	ENSP00000359878.5
	ACADM	ENST00000370834.9	TSL:1	c.588T>G	p.Pro196Pro	synonymous	Exon 8 of 13	ENSP00000359871.5
	ACADM	ENST00000420607.6	TSL:1	c.501T>G	p.Pro167Pro	synonymous	Exon 7 of 12	ENSP00000409612.2

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3020 AN: 152206 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00568 AC: 1425 AN: 250924 AF XY: 0.00406

Gnomad AFR exome AF: 0.0698

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000529

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00238 AC: 3471 AN: 1459894 Hom.: 101 Cov.: 30 AF XY: 0.00214 AC XY: 1554 AN XY: 726298

African (AFR) AF: 0.0684 AC: 2286 AN: 33406

American (AMR) AF: 0.00519 AC: 232 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86112

European-Finnish (FIN) AF: 0.000413 AC: 22 AN: 53322

Middle Eastern (MID) AF: 0.00834 AC: 48 AN: 5758

European-Non Finnish (NFE) AF: 0.000398 AC: 442 AN: 1110660

Other (OTH) AF: 0.00572 AC: 345 AN: 60312

GnomAD4 genome AF: 0.0199 AC: 3026 AN: 152324 Hom.: 116 Cov.: 33 AF XY: 0.0191 AC XY: 1419 AN XY: 74482

African (AFR) AF: 0.0675 AC: 2804 AN: 41558

American (AMR) AF: 0.00869 AC: 133 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68032

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00921 Hom.: 29

Bravo AF: 0.0219

Asia WGS AF: 0.00376 AC: 13 AN: 3472

EpiCase AF: 0.000873

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Medium-chain acyl-coenzyme A dehydrogenase deficiency (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.4
DANN	Benign	0.83
PhyloP100		-0.31
Mutation Taster		=292/8	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: rs78392995; hg19: chr1-76205685;