NM_000126.4:c.39+1285G>T

Variant names:

• chr15-76310065-C-A
• rs2469213
• NM_000126.4:c.39+1285G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000126.4(ETFA):​c.39+1285G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.000053 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ETFA NM_000126.4 intron
• Scores: Splicing: ADA: 0.00007896
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.917
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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+1285G>T		intron	N/A	NP_000117.1
	ETFA	NM_001127716.2		c.39+1285G>T		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+1285G>T		intron	N/A	ENSP00000452762.1
	ETFA	ENST00000560595.6	TSL:1	c.39+1285G>T		intron	N/A	ENSP00000453345.2
	ETFA	ENST00000692691.1		c.39+1285G>T		intron	N/A	ENSP00000508808.1

Frequencies

GnomAD3 genomes AF: 0.0000529 AC: 1 AN: 18904 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 812 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 594

African (AFR) AF: 0.00 AC: 0 AN: 24

American (AMR) AF: 0.00 AC: 0 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.00 AC: 0 AN: 70

South Asian (SAS) AF: 0.00 AC: 0 AN: 142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 506

Other (OTH) AF: 0.00 AC: 0 AN: 22

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000529 AC: 1 AN: 18904 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8814

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8588

American (AMR) AF: 0.00 AC: 0 AN: 1566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 470

East Asian (EAS) AF: 0.00 AC: 0 AN: 920

South Asian (SAS) AF: 0.00 AC: 0 AN: 602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.000169 AC: 1 AN: 5934

Other (OTH) AF: 0.00 AC: 0 AN: 220

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.5
DANN	Benign	0.62
PhyloP100		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -3

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

Other links and lift over

dbSNP: rs2469213; hg19: chr15-76602406;