chr2-26290089-G-C

Variant names:

• chr2-26290089-G-C
• rs1056471
• NM_000183.3:c.*136G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000183.3(HADHB):​c.*136G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 763,492 control chromosomes in the GnomAD database, including 293,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (59285 hom., cov: 33)
  • Exomes 𝑓: 0.85 (233964 hom.)
• Consequence: HADHB NM_000183.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.868
• Publications: 14 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), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-26290089-G-C is Benign according to our data. Variant chr2-26290089-G-C is described in ClinVar as Benign. ClinVar VariationId is 335410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000183.3. 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
	HADHB	NM_000183.3	MANE Select	c.*136G>C		3_prime_UTR	Exon 16 of 16	NP_000174.1	P55084-1
	HADHB	NM_001281512.2		c.*136G>C		3_prime_UTR	Exon 15 of 15	NP_001268441.1	F5GZQ3
	HADHB	NM_001281513.2		c.*136G>C		3_prime_UTR	Exon 17 of 17	NP_001268442.1	P55084-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHB	ENST00000317799.10	TSL:1 MANE Select	c.*136G>C		3_prime_UTR	Exon 16 of 16	ENSP00000325136.5	P55084-1
	HADHB	ENST00000942431.1		c.*136G>C		3_prime_UTR	Exon 17 of 17	ENSP00000612490.1
	HADHB	ENST00000942426.1		c.*136G>C		3_prime_UTR	Exon 16 of 16	ENSP00000612485.1

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132313 AN: 152162 Hom.: 59230 Cov.: 33

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.862

GnomAD4 exome AF: 0.853 AC: 521537 AN: 611212 Hom.: 233964 Cov.: 6 AF XY: 0.859 AC XY: 286689 AN XY: 333710

African (AFR) AF: 0.882 AC: 15227 AN: 17266

American (AMR) AF: 0.635 AC: 26754 AN: 42114

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 18619 AN: 20566

East Asian (EAS) AF: 0.162 AC: 5719 AN: 35300

South Asian (SAS) AF: 0.848 AC: 57743 AN: 68110

European-Finnish (FIN) AF: 0.941 AC: 37788 AN: 40146

Middle Eastern (MID) AF: 0.932 AC: 3225 AN: 3462

European-Non Finnish (NFE) AF: 0.933 AC: 328296 AN: 351750

Other (OTH) AF: 0.867 AC: 28166 AN: 32498

GnomAD4 genome AF: 0.870 AC: 132427 AN: 152280 Hom.: 59285 Cov.: 33 AF XY: 0.862 AC XY: 64218 AN XY: 74470

African (AFR) AF: 0.883 AC: 36698 AN: 41558

American (AMR) AF: 0.739 AC: 11294 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 3135 AN: 3470

East Asian (EAS) AF: 0.185 AC: 955 AN: 5168

South Asian (SAS) AF: 0.817 AC: 3947 AN: 4830

European-Finnish (FIN) AF: 0.938 AC: 9959 AN: 10616

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.933 AC: 63503 AN: 68032

Other (OTH) AF: 0.861 AC: 1818 AN: 2112

Alfa AF: 0.906 Hom.: 7841

Bravo AF: 0.850

Asia WGS AF: 0.585 AC: 2038 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mitochondrial trifunctional protein deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.8
DANN	Benign	0.82
PhyloP100		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1056471; hg19: chr2-26512957; COSMIC: COSV58546186;