chr15-76295584-T-C

Variant names:

• chr15-76295584-T-C
• rs184587113
• NM_000126.4:c.186+7A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The ENST00000557943.6(ETFA):​c.186+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,612,466 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0029 (6 hom.)
• Consequence: ETFA ENST00000557943.6 splice_region, intron
• Scores: Splicing: ADA: 0.0003460
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.641
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 15-76295584-T-C is Benign according to our data. Variant chr15-76295584-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203686.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00219 (333/152200) while in subpopulation AMR AF = 0.00373 (57/15276). AF 95% confidence interval is 0.00296. There are 0 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557943.6. 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.186+7A>G		splice_region intron	N/A	NP_000117.1
	ETFA	NM_001127716.2		c.40-2884A>G		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.186+7A>G		splice_region intron	N/A	ENSP00000452762.1
	ETFA	ENST00000560595.6	TSL:1	c.186+7A>G		splice_region intron	N/A	ENSP00000453345.2
	ETFA	ENST00000692691.1		c.186+7A>G		splice_region intron	N/A	ENSP00000508808.1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152082 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00156 AC: 392 AN: 251480 AF XY: 0.00133

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00288 AC: 4210 AN: 1460266 Hom.: 6 Cov.: 31 AF XY: 0.00275 AC XY: 1998 AN XY: 726590

African (AFR) AF: 0.000419 AC: 14 AN: 33446

American (AMR) AF: 0.000939 AC: 42 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86234

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53398

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00356 AC: 3958 AN: 1110558

Other (OTH) AF: 0.00189 AC: 114 AN: 60344

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152200 Hom.: 0 Cov.: 30 AF XY: 0.00238 AC XY: 177 AN XY: 74408

African (AFR) AF: 0.000866 AC: 36 AN: 41548

American (AMR) AF: 0.00373 AC: 57 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00329 AC: 224 AN: 67998

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00255

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Multiple acyl-CoA dehydrogenase deficiency (3)
-	-	2	not provided (2)
-	-	1	Glutaric acidemia type 2A (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.0
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: rs184587113; hg19: chr15-76587925;