rs113112630

Variant names:

• chr2-26263480-G-A
• rs113112630
• NM_000183.3:c.209+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26263480-G-A
• chr2-26263480-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000183.3(HADHB):​c.209+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000718 in 1,393,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: HADHB NM_000183.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.03
• Publications: 1 publications found

Genes affected

HADHB (HGNC:4803): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta) This gene encodes the beta subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the beta subunit catalyzing the 3-ketoacyl-CoA thiolase activity. The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. Mutations in this gene result in trifunctional protein deficiency. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

HADHB Gene-Disease associations (from GenCC):

• mitochondrial trifunctional protein deficiency

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 2-26263480-G-A is Pathogenic according to our data. Variant chr2-26263480-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 225385.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADHB	NM_000183.3	c.209+1G>A		splice_donor_variant, intron_variant	Intron 4 of 15	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.209+1G>A		splice_donor_variant, intron_variant	Intron 4 of 14		NP_001268441.1
HADHB	NM_001281513.2	c.143+1G>A		splice_donor_variant, intron_variant	Intron 5 of 16		NP_001268442.1
HADHB	XM_011532803.2	c.209+1G>A		splice_donor_variant, intron_variant	Intron 4 of 15		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.209+1G>A		splice_donor_variant, intron_variant	Intron 4 of 15	1	NM_000183.3	ENSP00000325136.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251476 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000718 AC: 10 AN: 1393052 Hom.: 0 Cov.: 25 AF XY: 0.00000144 AC XY: 1 AN XY: 696784

African (AFR) AF: 0.00 AC: 0 AN: 32252

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25724

East Asian (EAS) AF: 0.00 AC: 0 AN: 39352

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00000858 AC: 9 AN: 1049240

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000315 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial trifunctional protein deficiency Pathogenic:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.0
GERP RS		4.8
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs113112630; hg19: chr2-26486348;