rs7607527

Variant names:

• chr2-26279284-C-T
• rs7607527
• NM_000183.3:c.780C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000183.3(HADHB):​c.780C>T​(p.Leu260Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,612,892 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (12 hom.)
• Consequence: HADHB NM_000183.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.57
• Publications: 2 publications found

Genes affected

HADHB (HGNC:4803): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta) This gene encodes the beta 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 beta subunit catalyzing the 3-ketoacyl-CoA thiolase activity. The encoded protein can also bind RNA and decreases the stability of some mRNAs. 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. Mutations in this gene result in trifunctional protein deficiency. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

HADHB Gene-Disease associations (from GenCC):

• mitochondrial trifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 2-26279284-C-T is Benign according to our data. Variant chr2-26279284-C-T is described in ClinVar as Benign. ClinVar VariationId is 203748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00626 (953/152210) while in subpopulation AFR AF = 0.0215 (892/41522). AF 95% confidence interval is 0.0203. There are 7 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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_000183.3. 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
	HADHB	NM_000183.3	MANE Select	c.780C>T	p.Leu260Leu	synonymous	Exon 9 of 16	NP_000174.1	P55084-1
	HADHB	NM_001281512.2		c.735C>T	p.Leu245Leu	synonymous	Exon 8 of 15	NP_001268441.1	F5GZQ3
	HADHB	NM_001281513.2		c.714C>T	p.Leu238Leu	synonymous	Exon 10 of 17	NP_001268442.1	P55084-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHB	ENST00000317799.10	TSL:1 MANE Select	c.780C>T	p.Leu260Leu	synonymous	Exon 9 of 16	ENSP00000325136.5	P55084-1
	HADHB	ENST00000942431.1		c.864C>T	p.Leu288Leu	synonymous	Exon 10 of 17	ENSP00000612490.1
	HADHB	ENST00000942426.1		c.810C>T	p.Leu270Leu	synonymous	Exon 9 of 16	ENSP00000612485.1

Frequencies

GnomAD3 genomes AF: 0.00622 AC: 946 AN: 152092 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00581

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00239 AC: 602 AN: 251432 AF XY: 0.00224

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00103 AC: 1507 AN: 1460682 Hom.: 12 Cov.: 31 AF XY: 0.00115 AC XY: 835 AN XY: 726758

African (AFR) AF: 0.0207 AC: 693 AN: 33444

American (AMR) AF: 0.00110 AC: 49 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00685 AC: 591 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5762

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1110944

Other (OTH) AF: 0.00234 AC: 141 AN: 60342

GnomAD4 genome AF: 0.00626 AC: 953 AN: 152210 Hom.: 7 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74436

African (AFR) AF: 0.0215 AC: 892 AN: 41522

American (AMR) AF: 0.00144 AC: 22 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00282 Hom.: 1

Bravo AF: 0.00696

Asia WGS AF: 0.00808 AC: 31 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Mitochondrial trifunctional protein deficiency (2)
-	-	1	Mitochondrial trifunctional protein deficiency 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	6.7
DANN	Benign	0.70
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs7607527; hg19: chr2-26502152;