2-26190948-C-T

Variant names:

• chr2-26190948-C-T
• rs1049987
• NM_000182.5:c.*302G>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.*302G>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 0.195 in 511,080 control chromosomes in the GnomAD database, including 10,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2659 hom., cov: 33)
  • Exomes 𝑓: 0.20 (8064 hom.)
• Consequence: HADHA NM_000182.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0970
• Publications: 9 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=-0.74).
• BP6: Variant 2-26190948-C-T is Benign according to our data. Variant chr2-26190948-C-T is described in ClinVar as Benign. ClinVar VariationId is 335371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 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.*302G>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.*302G>A		3_prime_UTR	Exon 20 of 20	ENSP00000370023.3	P40939-1
	HADHA	ENST00000942149.1		c.*302G>A		3_prime_UTR	Exon 21 of 21	ENSP00000612208.1
	HADHA	ENST00000942146.1		c.*302G>A		3_prime_UTR	Exon 20 of 20	ENSP00000612205.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26512 AN: 152118 Hom.: 2655 Cov.: 33

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.203 AC: 73006 AN: 358844 Hom.: 8064 Cov.: 0 AF XY: 0.205 AC XY: 38875 AN XY: 189988

African (AFR) AF: 0.0624 AC: 666 AN: 10668

American (AMR) AF: 0.190 AC: 2992 AN: 15788

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 3436 AN: 10942

East Asian (EAS) AF: 0.114 AC: 2584 AN: 22700

South Asian (SAS) AF: 0.220 AC: 9506 AN: 43142

European-Finnish (FIN) AF: 0.272 AC: 5567 AN: 20464

Middle Eastern (MID) AF: 0.228 AC: 353 AN: 1548

European-Non Finnish (NFE) AF: 0.206 AC: 43765 AN: 212916

Other (OTH) AF: 0.200 AC: 4137 AN: 20676

GnomAD4 genome AF: 0.174 AC: 26534 AN: 152236 Hom.: 2659 Cov.: 33 AF XY: 0.179 AC XY: 13317 AN XY: 74422

African (AFR) AF: 0.0657 AC: 2731 AN: 41558

American (AMR) AF: 0.184 AC: 2822 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1069 AN: 3470

East Asian (EAS) AF: 0.143 AC: 743 AN: 5178

South Asian (SAS) AF: 0.213 AC: 1026 AN: 4824

European-Finnish (FIN) AF: 0.293 AC: 3107 AN: 10594

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14308 AN: 67990

Other (OTH) AF: 0.190 AC: 401 AN: 2114

Alfa AF: 0.196 Hom.: 1061

Bravo AF: 0.160

Asia WGS AF: 0.229 AC: 798 AN: 3478

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	-0.74
CADD	Benign	6.0
DANN	Benign	0.80
PhyloP100		-0.097
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: rs1049987; hg19: chr2-26413817;