rs2229420

Variant names:

• chr2-26209793-G-T
• rs2229420
• NM_000182.5:c.1072C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26209793-G-T
• chr2-26209793-G-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.1072C>A​(p.Gln358Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,540,490 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (129 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (83 hom.)
• Consequence: HADHA NM_000182.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.70
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037029982).
• BP6: Variant 2-26209793-G-T is Benign according to our data. Variant chr2-26209793-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.069 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.1072C>A	p.Gln358Lys	missense	Exon 11 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.1072C>A	p.Gln358Lys	missense	Exon 11 of 20	ENSP00000370023.3	P40939-1
	HADHA	ENST00000942149.1		c.1237C>A	p.Gln413Lys	missense	Exon 12 of 21	ENSP00000612208.1
	HADHA	ENST00000942146.1		c.1087C>A	p.Gln363Lys	missense	Exon 11 of 20	ENSP00000612205.1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3114 AN: 152140 Hom.: 128 Cov.: 32

Gnomad AFR AF: 0.0711

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00624 AC: 1568 AN: 251332 AF XY: 0.00525

Gnomad AFR exome AF: 0.0730

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00255 AC: 3535 AN: 1388232 Hom.: 83 Cov.: 25 AF XY: 0.00245 AC XY: 1701 AN XY: 695100

African (AFR) AF: 0.0697 AC: 2224 AN: 31914

American (AMR) AF: 0.00361 AC: 161 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.00706 AC: 598 AN: 84742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00515 AC: 29 AN: 5626

European-Non Finnish (NFE) AF: 0.000185 AC: 193 AN: 1044990

Other (OTH) AF: 0.00568 AC: 329 AN: 57912

GnomAD4 genome AF: 0.0205 AC: 3123 AN: 152258 Hom.: 129 Cov.: 32 AF XY: 0.0202 AC XY: 1504 AN XY: 74464

African (AFR) AF: 0.0712 AC: 2955 AN: 41512

American (AMR) AF: 0.00556 AC: 85 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68028

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00940 Hom.: 72

Bravo AF: 0.0236

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0667 AC: 294

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00754 AC: 915

Asia WGS AF: 0.00837 AC: 32 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (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
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.74
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.38	N
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.67
MPC		0.28
ClinPred		0.012	T
GERP RS		6.1
Varity_R		0.31
gMVP		0.56
Mutation Taster		=99/1	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: rs2229420; hg19: chr2-26432662;