1-75750501-C-T

Variant names:

• chr1-75750501-C-T
• rs17097429
• NM_000016.6:c.900C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000016.6(ACADM):​c.900C>T​(p.Thr300Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,612,472 control chromosomes in the GnomAD database, including 59 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. T300T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: ACADM NM_000016.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.151
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-75750501-C-T is Benign according to our data. Variant chr1-75750501-C-T is described in ClinVar as Benign. ClinVar VariationId is 136257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1715/152214) while in subpopulation AFR AF = 0.0393 (1634/41526). AF 95% confidence interval is 0.0378. There are 29 homozygotes in GnomAd4. There are 818 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

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.900C>T	p.Thr300Thr	synonymous	Exon 10 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.999C>T	p.Thr333Thr	synonymous	Exon 11 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.912C>T	p.Thr304Thr	synonymous	Exon 10 of 12	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.900C>T	p.Thr300Thr	synonymous	Exon 10 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.999C>T	p.Thr333Thr	synonymous	Exon 11 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.912C>T	p.Thr304Thr	synonymous	Exon 10 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1710 AN: 152096 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00303 AC: 759 AN: 250756 AF XY: 0.00216

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00117 AC: 1708 AN: 1460258 Hom.: 30 Cov.: 31 AF XY: 0.00105 AC XY: 761 AN XY: 726396

African (AFR) AF: 0.0406 AC: 1359 AN: 33436

American (AMR) AF: 0.00230 AC: 103 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00253 AC: 12 AN: 4740

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111866

Other (OTH) AF: 0.00279 AC: 168 AN: 60280

GnomAD4 genome AF: 0.0113 AC: 1715 AN: 152214 Hom.: 29 Cov.: 31 AF XY: 0.0110 AC XY: 818 AN XY: 74416

African (AFR) AF: 0.0393 AC: 1634 AN: 41526

American (AMR) AF: 0.00366 AC: 56 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00600 Hom.: 9

Bravo AF: 0.0130

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

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)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.1
DANN	Benign	0.52
PhyloP100		-0.15
Mutation Taster		=97/3	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: rs17097429; hg19: chr1-76216186;