15-76231389-T-G

Position:

• chr15-76231389-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000126.4(ETFA):​c.826A>C​(p.Ile276Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,597,636 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: ETFA NM_000126.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 6.62

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]

ETFA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026123345).
• BP6: Variant 15-76231389-T-G is Benign according to our data. Variant chr15-76231389-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203692.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00101 (154/152348) while in subpopulation NFE AF= 0.0015 (102/68032). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETFA	NM_000126.4	c.826A>C	p.Ile276Leu	missense_variant	10/12	ENST00000557943.6	NP_000117.1
ETFA	NM_001127716.2	c.679A>C	p.Ile227Leu	missense_variant	9/11		NP_001121188.1
ETFA	XR_007064434.1	n.907A>C		non_coding_transcript_exon_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFA	ENST00000557943.6	c.826A>C	p.Ile276Leu	missense_variant	10/12	1	NM_000126.4	ENSP00000452762.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00128 AC: 322 AN: 251268 Hom.: 0 AF XY: 0.00130 AC XY: 177 AN XY: 135826

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00115 AC: 1665 AN: 1445288 Hom.: 5 Cov.: 26 AF XY: 0.00121 AC XY: 873 AN XY: 720128

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00565

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000629

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74510

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00180 Hom.: 3

Bravo AF: 0.00115

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00366

EpiControl AF: 0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2020

- -

ETFA-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;.;T;.;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.8	L;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.12	T;T;T;D;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.040	B;.;.;.;.
Vest4		0.83
MVP		0.88
MPC		0.67
ClinPred		0.024	T
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.0
Varity_R		0.80
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs141200145; hg19: chr15-76523730;