rs760423996

Variant names:

• chr10-123051189-A-G
• rs760423996
• NM_001609.4:c.1128+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-123051189-A-G
• chr10-123051189-A-T
• chr10-123051189-A-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001609.4(ACADSB):​c.1128+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACADSB NM_001609.4 splice_region, intron
• Scores: Splicing: ADA: 0.9483
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.38
• Publications: 1 publications found

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]

ACADSB Gene-Disease associations (from GenCC):

• 2-methylbutyryl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001609.4. 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
	ACADSB	NM_001609.4	MANE Select	c.1128+3A>G		splice_region intron	N/A	NP_001600.1	P45954-1
	ACADSB	NM_001330174.3		c.822+3A>G		splice_region intron	N/A	NP_001317103.1	P45954-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADSB	ENST00000358776.7	TSL:1 MANE Select	c.1128+3A>G		splice_region intron	N/A	ENSP00000357873.3	P45954-1
	ACADSB	ENST00000908753.1		c.1035+3A>G		splice_region intron	N/A	ENSP00000578812.1
	ACADSB	ENST00000908750.1		c.991-1872A>G		intron	N/A	ENSP00000578809.1

Frequencies

GnomAD3 genomes AF: 0.0000242 AC: 1 AN: 41316 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000519

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000249 AC: 6 AN: 24094 AF XY: 0.000146

Gnomad AFR exome AF: 0.000776

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000265 AC: 9 AN: 33912 Hom.: 0 Cov.: 0 AF XY: 0.000333 AC XY: 6 AN XY: 18006

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 736

American (AMR) AF: 0.00 AC: 0 AN: 824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1268

East Asian (EAS) AF: 0.00 AC: 0 AN: 296

South Asian (SAS) AF: 0.00 AC: 0 AN: 4676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 78

European-Non Finnish (NFE) AF: 0.000385 AC: 9 AN: 23384

Other (OTH) AF: 0.00 AC: 0 AN: 1194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000569917), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000242 AC: 1 AN: 41316 Hom.: 0 Cov.: 0 AF XY: 0.0000521 AC XY: 1 AN XY: 19186

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10488

American (AMR) AF: 0.00 AC: 0 AN: 3826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1386

East Asian (EAS) AF: 0.00 AC: 0 AN: 3094

South Asian (SAS) AF: 0.00 AC: 0 AN: 930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.0000519 AC: 1 AN: 19276

Other (OTH) AF: 0.00 AC: 0 AN: 570

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Deficiency of 2-methylbutyryl-CoA dehydrogenase (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.79
PhyloP100		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.18		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: rs760423996; hg19: chr10-124810705;