rs57969630

Variant names:

• chr2-26280012-A-G
• rs57969630
• NM_000183.3:c.830A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000183.3(HADHB):​c.830A>G​(p.Lys277Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00149 in 1,609,410 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (10 hom.)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.10
• Publications: 5 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.64924 (below the threshold of 3.09). Trascript score misZ: 0.82597 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial trifunctional protein deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.012434572).
• BP6: Variant 2-26280012-A-G is Benign according to our data. Variant chr2-26280012-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 203750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00628 (957/152320) while in subpopulation AFR AF = 0.0215 (894/41582). AF 95% confidence interval is 0.0203. There are 7 homozygotes in GnomAd4. There are 445 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.830A>G	p.Lys277Arg	missense	Exon 10 of 16	NP_000174.1	P55084-1
	HADHB	NM_001281512.2		c.785A>G	p.Lys262Arg	missense	Exon 9 of 15	NP_001268441.1	F5GZQ3
	HADHB	NM_001281513.2		c.764A>G	p.Lys255Arg	missense	Exon 11 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.830A>G	p.Lys277Arg	missense	Exon 10 of 16	ENSP00000325136.5	P55084-1
	HADHB	ENST00000942431.1		c.914A>G	p.Lys305Arg	missense	Exon 11 of 17	ENSP00000612490.1
	HADHB	ENST00000942426.1		c.860A>G	p.Lys287Arg	missense	Exon 10 of 16	ENSP00000612485.1

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152202 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00240 AC: 604 AN: 251352 AF XY: 0.00225

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000991 AC: 1444 AN: 1457090 Hom.: 10 Cov.: 29 AF XY: 0.00112 AC XY: 811 AN XY: 725124

African (AFR) AF: 0.0198 AC: 661 AN: 33328

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00673 AC: 579 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000227 AC: 1 AN: 4408

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1109236

Other (OTH) AF: 0.00228 AC: 137 AN: 60124

GnomAD4 genome AF: 0.00628 AC: 957 AN: 152320 Hom.: 7 Cov.: 32 AF XY: 0.00597 AC XY: 445 AN XY: 74478

African (AFR) AF: 0.0215 AC: 894 AN: 41582

American (AMR) AF: 0.00144 AC: 22 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00265 Hom.: 10

Bravo AF: 0.00697

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0195 AC: 86

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00276 AC: 335

Asia WGS AF: 0.00924 AC: 35 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Benign	0.27	N
PhyloP100		7.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.34
Sift	Benign	0.32	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.16
MVP		0.89
MPC		0.11
ClinPred		0.032	T
GERP RS		5.4
Varity_R		0.30
gMVP		0.51
Mutation Taster		=97/3	polymorphism

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: rs57969630; hg19: chr2-26502880;