rs146210168

Variant names:

• chr2-26190847-G-A
• rs146210168
• NM_000182.5:c.*403C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000182.5(HADHA):​c.*403C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000071 in 295,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: HADHA NM_000182.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.380
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

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.*403C>T		3_prime_UTR	Exon 20 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.*403C>T		3_prime_UTR	Exon 20 of 20	ENSP00000370023.3	P40939-1
	HADHA	ENST00000492433.2	TSL:2	c.*403C>T		3_prime_UTR	Exon 19 of 19	ENSP00000438039.2	H0YFD6
	HADHA	ENST00000859324.1		c.*403C>T		3_prime_UTR	Exon 20 of 20	ENSP00000529383.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000557 AC: 8 AN: 143566 Hom.: 0 Cov.: 0 AF XY: 0.0000526 AC XY: 4 AN XY: 76038

African (AFR) AF: 0.00 AC: 0 AN: 4752

American (AMR) AF: 0.00 AC: 0 AN: 5908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3658

East Asian (EAS) AF: 0.000605 AC: 4 AN: 6610

South Asian (SAS) AF: 0.00 AC: 0 AN: 21864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 540

European-Non Finnish (NFE) AF: 0.0000466 AC: 4 AN: 85818

Other (OTH) AF: 0.00 AC: 0 AN: 7442

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

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

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (1)
-	1	-	Mitochondrial trifunctional protein deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.49
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs146210168; hg19: chr2-26413716;