NM_000182.5:c.1086-3_1092delCAGGCATCTG

Variant names:

• chr2-26204189-CCAGATGCCTG-C
• rs1057516460
• NM_000182.5:c.1086-3_1092delCAGGCATCTG

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.1086-3_1092delCAGGCATCTG​(p.His363fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HADHA NM_000182.5 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.32
• Publications: 0 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]

GAREM2 (HGNC:27172): (GRB2 associated regulator of MAPK1 subtype 2)

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 2-26204189-CCAGATGCCTG-C is Pathogenic according to our data. Variant chr2-26204189-CCAGATGCCTG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 370400.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	NM_000182.5	MANE Select	c.1086-3_1092delCAGGCATCTG	p.His363fs	frameshift splice_acceptor splice_region intron	Exon 12 of 20	NP_000173.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	ENST00000380649.8	TSL:1 MANE Select	c.1086-3_1092delCAGGCATCTG	p.His363fs	frameshift splice_acceptor splice_region intron	Exon 12 of 20	ENSP00000370023.3
	HADHA	ENST00000942149.1		c.1251-3_1257delCAGGCATCTG	p.His418fs	frameshift splice_acceptor splice_region intron	Exon 13 of 21	ENSP00000612208.1
	HADHA	ENST00000942146.1		c.1101-3_1107delCAGGCATCTG	p.His368fs	frameshift splice_acceptor splice_region intron	Exon 12 of 20	ENSP00000612205.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461604 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727126

⚠️ 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: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111760

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000546988), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (3)
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
PhyloP100		9.3
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1057516460; hg19: chr2-26427058;