chr10-123037848-G-A

Variant names:

• chr10-123037848-G-A
• rs147936696
• NM_001609.4:c.303+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001609.4(ACADSB):​c.303+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,556,270 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: ACADSB NM_001609.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:1
• Conservation: PhyloP100: 9.56

Genes affected

ACADSB (HGNC:91): (acyl-CoA dehydrogenase short/branched chain) Short/branched chain acyl-CoA dehydrogenase(ACADSB) is a member of the acyl-CoA dehydrogenase family of enzymes that catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. Substrate specificity is the primary characteristic used to define members of this gene family. The ACADSB gene product has the greatest activity towards the short branched chain acyl-CoA derivative, (S)-2-methylbutyryl-CoA, but also reacts significantly with other 2-methyl branched chain substrates and with short straight chain acyl-CoAs. The cDNA encodes for a mitochondrial precursor protein which is cleaved upon mitochondrial import and predicted to yield a mature peptide of approximately 43.7-KDa. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-123037848-G-A is Pathogenic according to our data. Variant chr10-123037848-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203367.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=5}. Variant chr10-123037848-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADSB	NM_001609.4	c.303+1G>A		splice_donor_variant, intron_variant	Intron 3 of 10	ENST00000358776.7	NP_001600.1
ACADSB	NM_001330174.3	c.-3-2618G>A		intron_variant	Intron 2 of 9		NP_001317103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADSB	ENST00000358776.7	c.303+1G>A		splice_donor_variant, intron_variant	Intron 3 of 10	1	NM_001609.4	ENSP00000357873.3
ACADSB	ENST00000368869.8	c.-3-2618G>A		intron_variant	Intron 2 of 9	2		ENSP00000357862.4
ACADSB	ENST00000411816.2	n.320+1G>A		splice_donor_variant, intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251174 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135802

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000444 AC: 623 AN: 1404192 Hom.: 1 Cov.: 26 AF XY: 0.000455 AC XY: 319 AN XY: 701580

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000549

Gnomad4 OTH exome AF: 0.000495

GnomAD4 genome AF: 0.000362 AC: 55 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74284

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000932 AC: 8

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase Pathogenic:10

Feb 22, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.303+1G>A variant in ACADSB has been reported in the homozygous state in 2 individual with short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency; both showed the biochemical phenotype but only one showed clinical symptoms (Alfardan 2010 PMID: 20547083). It has also been reported in the homozygous state in 2 siblings without clinical symptoms (Spedicati 2021 PMID: 33727708). It has been identified in 0.056% (628/1127804) of European (non-Finnish) chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Computational prediction tools and conservation analyses are consistent with pathogenicity. Biallelic loss-of-function of the ACADSB gene is an established disease mechanism in autosomal recessive SBCAD deficiency. SBCAD deficiency results in a biochemical phenotype that be detected from birth; however, the clinical significance of this is unclear. 90% of individuals with SBCAD deficiency have no clinical symptoms, and the remaining 10% may display developmental delay and/or neurological disorders. These 10% of individuals may represent extreme end of the clinical spectrum or coincidental findings (Porta 2019 PMID: 30730842, Alfardan 2010 PMID: 20547083). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive SBCAD deficiency. ACMG/AMP Criteria applied: PVS1, PM3_Supporting. -

Nov 12, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -

Jul 17, 2014

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This patient is a carrier of a heterozygous pathogenic variant in the ACADSB gene associated with 2-methylbutyrylglycinuria. The ACADSB variant (c.303+1G>A) identified in this patient is located in the first intronic position of the donor splice site and, therefore, meets the criteria for a pathogenic variant. -

Dec 03, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADSB c.303+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.303+1G>A variant has been reported in one study in which it was found in a homozygous state in two individuals with acyl-CoA dehydrogenase deficiency, oneof whom was symptomatic and the other asymptomatic newborn (Alfardan et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000931 in the European American population of the Exome Sequencing Project. Based on the potential impact of splice donor variants and the clinical evidence, the c.303+1G>A variant is classified as likely pathogenic for acyl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 18, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 15, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADSB c.303+1G>A variant, also known as IVS3+1G>A, has been reported in the homozygous state in two individuals, one individual with a clinical diagnosis of methylbutyryl-CoA dehydrogenase deficiency and the other individual identified by newborn screening (Alfardan J et al., PMID: 20547083). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by eight submitters. This variant is only observed on 77/282,550 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs within the canonical splice donor site, which is predicted to cause skipping of the exon, leading to an out of frame transcript. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -

Jun 01, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADSB c.303+1G>A (also described as IVS3+1G>A in the literature) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of ACADSB function. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 251174 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ACADSB causing Deficiency of 2-methylbutyryl-CoA Dehydrogenase (0.00025 vs 0.0011), allowing no conclusion about variant significance. c.303+1G>A has been reported in the literature in two homozygous individuals (an asymptomatic infant and a symptomatic individual) with deficiency of 2-methylbutyryl-CoA Dehydrogenase (Alfardan_2010). It has also been reported in the homozygous state in 2 siblings without clinical symptoms (Spedicati_2021). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20547083, 31980526, 33727708). ClinVar contains an entry for this variant (Variation ID: 203367). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 3 of the ACADSB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADSB are known to be pathogenic (PMID: 20547083, 26284228). This variant is present in population databases (rs147936696, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency (PMID: 20547083). This variant is also known as IVS3+1G>A. ClinVar contains an entry for this variant (Variation ID: 203367). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:1

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 31589614, 33727708, 20547083, 34493867) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs147936696; hg19: chr10-124797364;