rs137852775

Variant names:

• chr2-26214490-G-A
• rs137852775
• NM_000182.5:c.871C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26214490-G-A
• chr2-26214490-G-C
• chr2-26214490-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000182.5(HADHA):​c.871C>T​(p.Arg291*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000826 in 1,452,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: HADHA NM_000182.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.31
• Publications: 6 publications found

Genes affected

HADHA (HGNC:4801): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) This gene encodes the alpha 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 alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. 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. [provided by RefSeq, Jul 2008]

HADHA Gene-Disease associations (from GenCC):

• long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• mitochondrial trifunctional protein deficiency

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26214490-G-A is Pathogenic according to our data. Variant chr2-26214490-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000182.5. 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
	HADHA	NM_000182.5	MANE Select	c.871C>T	p.Arg291*	stop_gained	Exon 9 of 20	NP_000173.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	ENST00000380649.8	TSL:1 MANE Select	c.871C>T	p.Arg291*	stop_gained	Exon 9 of 20	ENSP00000370023.3	P40939-1
	HADHA	ENST00000942149.1		c.871C>T	p.Arg291*	stop_gained	Exon 9 of 21	ENSP00000612208.1
	HADHA	ENST00000942146.1		c.886C>T	p.Arg296*	stop_gained	Exon 9 of 20	ENSP00000612205.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000826 AC: 12 AN: 1452922 Hom.: 0 Cov.: 29 AF XY: 0.00000968 AC XY: 7 AN XY: 723366

⚠️ 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: 33284

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

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

Middle Eastern (MID) AF: 0.000214 AC: 1 AN: 4682

European-Non Finnish (NFE) AF: 0.00000814 AC: 9 AN: 1105074

Other (OTH) AF: 0.00 AC: 0 AN: 60010

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000170058), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (4)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mitochondrial trifunctional protein deficiency 1 (1)
1	-	-	Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		4.3
Vest4		0.92
GERP RS		3.4
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852775; hg19: chr2-26437359; COSMIC: COSV66106265; COSMIC: COSV66106265;