2-26191048-C-T

Variant names:

• chr2-26191048-C-T
• rs7260
• NM_000182.5:c.*202G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000182.5(HADHA):​c.*202G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 644,272 control chromosomes in the GnomAD database, including 195,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45038 hom., cov: 32)
  • Exomes 𝑓: 0.78 (150945 hom.)
• Consequence: HADHA NM_000182.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.73
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-26191048-C-T is Benign according to our data. Variant chr2-26191048-C-T is described in ClinVar as Benign. ClinVar VariationId is 335372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

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.*202G>A		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.*202G>A		3_prime_UTR	Exon 20 of 20	ENSP00000370023.3	P40939-1
	HADHA	ENST00000942149.1		c.*202G>A		3_prime_UTR	Exon 21 of 21	ENSP00000612208.1
	HADHA	ENST00000942146.1		c.*202G>A		3_prime_UTR	Exon 20 of 20	ENSP00000612205.1

Frequencies

GnomAD3 genomes AF: 0.770 AC: 116987 AN: 152002 Hom.: 45019 Cov.: 32

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.777

Gnomad FIN AF: 0.704

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.774

GnomAD4 exome AF: 0.782 AC: 384750 AN: 492152 Hom.: 150945 Cov.: 4 AF XY: 0.781 AC XY: 204154 AN XY: 261286

African (AFR) AF: 0.754 AC: 10840 AN: 14368

American (AMR) AF: 0.783 AC: 22724 AN: 29010

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 10697 AN: 15802

East Asian (EAS) AF: 0.876 AC: 27439 AN: 31318

South Asian (SAS) AF: 0.768 AC: 39570 AN: 51528

European-Finnish (FIN) AF: 0.723 AC: 22066 AN: 30502

Middle Eastern (MID) AF: 0.744 AC: 1595 AN: 2144

European-Non Finnish (NFE) AF: 0.788 AC: 228306 AN: 289720

Other (OTH) AF: 0.775 AC: 21513 AN: 27760

GnomAD4 genome AF: 0.770 AC: 117059 AN: 152120 Hom.: 45038 Cov.: 32 AF XY: 0.766 AC XY: 56945 AN XY: 74342

African (AFR) AF: 0.753 AC: 31257 AN: 41502

American (AMR) AF: 0.781 AC: 11951 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2391 AN: 3466

East Asian (EAS) AF: 0.846 AC: 4368 AN: 5162

South Asian (SAS) AF: 0.777 AC: 3746 AN: 4822

European-Finnish (FIN) AF: 0.704 AC: 7452 AN: 10578

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.785 AC: 53393 AN: 67982

Other (OTH) AF: 0.772 AC: 1627 AN: 2108

Alfa AF: 0.777 Hom.: 12762

Bravo AF: 0.774

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.84
CADD	Benign	0.48
DANN	Benign	0.68
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs7260; hg19: chr2-26413917;