15-76231389-T-G

Variant names:

• chr15-76231389-T-G
• rs141200145
• NM_000126.4:c.826A>C

Variant summary

Our verdict is Benign. The variant received -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:3 B:5
• Conservation: PhyloP100: 6.62
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• multiple acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 203692.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000126.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFA	NM_000126.4	MANE Select	c.826A>C	p.Ile276Leu	missense	Exon 10 of 12	NP_000117.1
	ETFA	NM_001127716.2		c.679A>C	p.Ile227Leu	missense	Exon 9 of 11	NP_001121188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFA	ENST00000557943.6	TSL:1 MANE Select	c.826A>C	p.Ile276Leu	missense	Exon 10 of 12	ENSP00000452762.1
	ETFA	ENST00000560595.6	TSL:1	c.1045A>C	p.Ile349Leu	missense	Exon 12 of 14	ENSP00000453345.2
	ETFA	ENST00000692691.1		c.949A>C	p.Ile317Leu	missense	Exon 11 of 13	ENSP00000508808.1

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

GnomAD2 exomes AF: 0.00128 AC: 322 AN: 251268 AF XY: 0.00130

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 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

African (AFR) AF: 0.000181 AC: 6 AN: 33180

American (AMR) AF: 0.00181 AC: 81 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00565 AC: 147 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.000629 AC: 54 AN: 85856

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53372

Middle Eastern (MID) AF: 0.0143 AC: 82 AN: 5718

European-Non Finnish (NFE) AF: 0.00108 AC: 1187 AN: 1097082

Other (OTH) AF: 0.00174 AC: 104 AN: 59770

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

African (AFR) AF: 0.000192 AC: 8 AN: 41584

American (AMR) AF: 0.00111 AC: 17 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00173 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	Multiple acyl-CoA dehydrogenase deficiency (6)
-	-	1	ETFA-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.60
Sift	Benign	0.12	T
Sift4G	Benign	0.14	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
Mutation Taster		=34/66	disease causing

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: rs141200145; hg19: chr15-76523730;