rs60085478

Variant names:

• chr2-26201139-C-T
• rs60085478
• NM_000182.5:c.1392+10G>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.1392+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,603,088 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (119 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (101 hom.)
• Consequence: HADHA NM_000182.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.699
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-26201139-C-T is Benign according to our data. Variant chr2-26201139-C-T is described in ClinVar as Benign. ClinVar VariationId is 203738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0701 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	NM_000182.5	MANE Select	c.1392+10G>A		intron	N/A	NP_000173.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHA	ENST00000380649.8	TSL:1 MANE Select	c.1392+10G>A		intron	N/A	ENSP00000370023.3
	HADHA	ENST00000492433.2	TSL:2	c.1392+10G>A		intron	N/A	ENSP00000438039.2
	HADHA	ENST00000645274.1		c.1287+10G>A		intron	N/A	ENSP00000493996.1

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3173 AN: 152168 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00592 AC: 1488 AN: 251230 AF XY: 0.00437

Gnomad AFR exome AF: 0.0770

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00233 AC: 3383 AN: 1450802 Hom.: 101 Cov.: 29 AF XY: 0.00196 AC XY: 1414 AN XY: 722430

African (AFR) AF: 0.0779 AC: 2590 AN: 33228

American (AMR) AF: 0.00374 AC: 167 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00545 AC: 142 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5752

European-Non Finnish (NFE) AF: 0.000127 AC: 140 AN: 1101998

Other (OTH) AF: 0.00513 AC: 308 AN: 60008

GnomAD4 genome AF: 0.0209 AC: 3182 AN: 152286 Hom.: 119 Cov.: 32 AF XY: 0.0198 AC XY: 1471 AN XY: 74458

African (AFR) AF: 0.0723 AC: 3004 AN: 41548

American (AMR) AF: 0.00758 AC: 116 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68036

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0130 Hom.: 37

Bravo AF: 0.0240

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Mitochondrial trifunctional protein deficiency (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_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.56
PhyloP100		0.70
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: rs60085478; hg19: chr2-26424008;