2-26289945-C-T

Variant names:

• chr2-26289945-C-T
• rs942477332
• NM_000183.3:c.1417C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000183.3(HADHB):​c.1417C>T​(p.Pro473Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,140 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: HADHB NM_000183.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADHB	NM_000183.3	c.1417C>T	p.Pro473Ser	missense_variant	Exon 16 of 16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.1372C>T	p.Pro458Ser	missense_variant	Exon 15 of 15		NP_001268441.1
HADHB	NM_001281513.2	c.1351C>T	p.Pro451Ser	missense_variant	Exon 17 of 17		NP_001268442.1
HADHB	XM_011532803.2	c.1417C>T	p.Pro473Ser	missense_variant	Exon 16 of 16		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.1417C>T	p.Pro473Ser	missense_variant	Exon 16 of 16	1	NM_000183.3	ENSP00000325136.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T;D;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.4	.;L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		1.0	D;D;B;.
Vest4		0.44
MutPred		0.37		.;Loss of sheet (P = 0.0357);.;.;
MVP		0.99
MPC		0.61
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs942477332; hg19: chr2-26512813;