rs764942250

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3PM2PP3PP5

The NM_000016.6(ACADM):​c.388-3T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002047267: Assessment of experimental evidence suggests this variant results in abnormal protein function.".

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

ACADM
NM_000016.6 splice_region, intron

Scores

2
Splicing: ADA: 0.9918
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 0.193

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PS3
PS3 evidence extracted from ClinVar submissions: SCV002047267: Assessment of experimental evidence suggests this variant results in abnormal protein function.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-75734788-T-G is Pathogenic according to our data. Variant chr1-75734788-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226079.

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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
ACADM
NM_000016.6
MANE Select
c.388-3T>G
splice_region intron
N/ANP_000007.1A0A0S2Z366
ACADM
NM_001286043.2
c.487-3T>G
splice_region intron
N/ANP_001272972.1Q5T4U5
ACADM
NM_001127328.3
c.400-3T>G
splice_region intron
N/ANP_001120800.1P11310-2

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
ACADM
ENST00000370841.9
TSL:1 MANE Select
c.388-3T>G
splice_region intron
N/AENSP00000359878.5P11310-1
ACADM
ENST00000370834.9
TSL:1
c.487-3T>G
splice_region intron
N/AENSP00000359871.5Q5T4U5
ACADM
ENST00000420607.6
TSL:1
c.400-3T>G
splice_region intron
N/AENSP00000409612.2P11310-2

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD2 exomes
AF:
0.0000399
AC:
10
AN:
250662
AF XY:
0.0000443
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000686
AC:
10
AN:
1458400
Hom.:
0
Cov.:
29
AF XY:
0.00000827
AC XY:
6
AN XY:
725706
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33420
American (AMR)
AF:
0.000157
AC:
7
AN:
44698
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26106
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39648
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86114
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53354
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5728
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1109090
Other (OTH)
AF:
0.0000498
AC:
3
AN:
60242
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.460
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
30
Alfa
AF:
0.000102
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

ClinVar submissions
Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
3
2
-
Medium-chain acyl-coenzyme A dehydrogenase deficiency (5)
-
1
-
ACADM-related disorder (1)
1
-
-
not provided (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
CADD
Benign
15
DANN
Benign
0.75
PhyloP100
0.19
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=7/93
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.76
SpliceAI score (max)
0.78
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.78
Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs764942250; hg19: chr1-76200473; COSMIC: COSV106514922; COSMIC: COSV106514922; API
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.