rs1801591

Positions:

• chr15-76286421-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The ENST00000557943.6(ETFA):​c.512C>T​(p.Thr171Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0821 in 1,612,408 control chromosomes in the GnomAD database, including 6,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T171T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.064 (433 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5685 hom.)
• Consequence: ETFA ENST00000557943.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.47

Genes affected

ETFA (HGNC:3481): (electron transfer flavoprotein subunit alpha) ETFA participates in catalyzing the initial step of the mitochondrial fatty acid beta-oxidation. It shuttles electrons between primary flavoprotein dehydrogenases and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Defects in electron-transfer-flavoprotein have been implicated in type II glutaricaciduria in which multiple acyl-CoA dehydrogenase deficiencies result in large excretion of glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.004926473).
• BP6: Variant 15-76286421-G-A is Benign according to our data. Variant chr15-76286421-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-76286421-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETFA	NM_000126.4	c.512C>T	p.Thr171Ile	missense_variant	6/12	ENST00000557943.6	NP_000117.1
ETFA	NM_001127716.2	c.365C>T	p.Thr122Ile	missense_variant	5/11		NP_001121188.1
ETFA	XR_007064434.1	n.593C>T		non_coding_transcript_exon_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFA	ENST00000557943.6	c.512C>T	p.Thr171Ile	missense_variant	6/12	1	NM_000126.4	ENSP00000452762	P1

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 9783 AN: 152150 Hom.: 433 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0422

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.0578

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0910

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.0736 AC: 18483 AN: 251282 Hom.: 810 AF XY: 0.0757 AC XY: 10285 AN XY: 135808

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.0325

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.0552

Gnomad SAS exome AF: 0.0675

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0907

Gnomad OTH exome AF: 0.0812

GnomAD4 exome AF: 0.0840 AC: 122594 AN: 1460138 Hom.: 5685 Cov.: 30 AF XY: 0.0837 AC XY: 60798 AN XY: 726474

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.0327

Gnomad4 ASJ exome AF: 0.0366

Gnomad4 EAS exome AF: 0.0540

Gnomad4 SAS exome AF: 0.0659

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.0903

Gnomad4 OTH exome AF: 0.0745

GnomAD4 genome AF: 0.0643 AC: 9790 AN: 152270 Hom.: 433 Cov.: 32 AF XY: 0.0663 AC XY: 4933 AN XY: 74446

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0422

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.0571

Gnomad4 SAS AF: 0.0696

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.0910

Gnomad4 OTH AF: 0.0606

Alfa AF: 0.0826 Hom.: 1152

Bravo AF: 0.0538

TwinsUK AF: 0.0920 AC: 341

ALSPAC AF: 0.0851 AC: 328

ESP6500AA AF: 0.0171 AC: 75

ESP6500EA AF: 0.0857 AC: 736

ExAC AF: 0.0761 AC: 9241

Asia WGS AF: 0.0720 AC: 253 AN: 3478

EpiCase AF: 0.0806

EpiControl AF: 0.0763

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;.;.;D;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
MetaRNN	Benign	0.0049	T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	4.1	H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.45
MPC		1.2
ClinPred		0.12	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1801591; hg19: chr15-76578762; COSMIC: COSV51211583; COSMIC: COSV51211583;