rs4886791

Variant names:

• chr15-76303909-C-T
• rs4886791
• NM_000126.4:c.39+7441G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000126.4(ETFA):​c.39+7441G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 152,152 control chromosomes in the GnomAD database, including 5,846 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5846 hom., cov: 32)
• Consequence: ETFA NM_000126.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.256
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

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.39+7441G>A		intron	N/A	NP_000117.1
	ETFA	NM_001127716.2		c.39+7441G>A		intron	N/A	NP_001121188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFA	ENST00000557943.6	TSL:1 MANE Select	c.39+7441G>A		intron	N/A	ENSP00000452762.1
	ETFA	ENST00000560595.6	TSL:1	c.39+7441G>A		intron	N/A	ENSP00000453345.2
	ETFA	ENST00000692691.1		c.39+7441G>A		intron	N/A	ENSP00000508808.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39514 AN: 152036 Hom.: 5839 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.265

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.260 AC: 39530 AN: 152152 Hom.: 5846 Cov.: 32 AF XY: 0.267 AC XY: 19870 AN XY: 74378

African (AFR) AF: 0.157 AC: 6519 AN: 41536

American (AMR) AF: 0.304 AC: 4636 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1069 AN: 3468

East Asian (EAS) AF: 0.575 AC: 2975 AN: 5170

South Asian (SAS) AF: 0.507 AC: 2447 AN: 4828

European-Finnish (FIN) AF: 0.284 AC: 3001 AN: 10572

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17944 AN: 67990

Other (OTH) AF: 0.265 AC: 559 AN: 2108

Alfa AF: 0.261 Hom.: 3100

Bravo AF: 0.255

Asia WGS AF: 0.518 AC: 1801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.75
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs4886791; hg19: chr15-76596250;