rs115151034

Variant names:

• chr2-26190689-G-A
• rs115151034
• NM_000182.5:c.*561C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000182.5(HADHA):​c.*561C>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 0.00498 in 152,302 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HADHA NM_000182.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.15
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-26190689-G-A is Benign according to our data. Variant chr2-26190689-G-A is described in ClinVar as Benign. ClinVar VariationId is 895645.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00498 (758/152302) while in subpopulation AFR AF = 0.0172 (714/41566). AF 95% confidence interval is 0.0161. There are 7 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.*561C>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.*561C>T		3_prime_UTR	Exon 20 of 20	ENSP00000370023.3	P40939-1
	HADHA	ENST00000492433.2	TSL:2	c.*561C>T		3_prime_UTR	Exon 19 of 19	ENSP00000438039.2	H0YFD6
	HADHA	ENST00000859324.1		c.*561C>T		3_prime_UTR	Exon 20 of 20	ENSP00000529383.1

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 757 AN: 152184 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 12954 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6642

African (AFR) AF: 0.00 AC: 0 AN: 152

American (AMR) AF: 0.00 AC: 0 AN: 2468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 92

East Asian (EAS) AF: 0.00 AC: 0 AN: 766

South Asian (SAS) AF: 0.00 AC: 0 AN: 1432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 7196

Other (OTH) AF: 0.00 AC: 0 AN: 560

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152302 Hom.: 7 Cov.: 33 AF XY: 0.00497 AC XY: 370 AN XY: 74480

African (AFR) AF: 0.0172 AC: 714 AN: 41566

American (AMR) AF: 0.00190 AC: 29 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00271 Hom.: 1

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	-0.88
CADD	Benign	0.72
DANN	Benign	0.55
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs115151034; hg19: chr2-26413558;