rs1801591

Variant names:

• chr15-76286421-G-A
• rs1801591
• NM_000126.4:c.512C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The NM_000126.4(ETFA):​c.512C>T​(p.Thr171Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0821 in 1,612,408 control chromosomes in the GnomAD database, including 6,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T171T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.064 (433 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5685 hom.)
• Consequence: ETFA NM_000126.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.47
• Publications: 43 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.004926473).
• BP6: Variant 15-76286421-G-A is Benign according to our data. Variant chr15-76286421-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0891 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFA	NM_000126.4	MANE Select	c.512C>T	p.Thr171Ile	missense	Exon 6 of 12	NP_000117.1	P13804-1
	ETFA	NM_001127716.2		c.365C>T	p.Thr122Ile	missense	Exon 5 of 11	NP_001121188.1	P13804-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFA	ENST00000557943.6	TSL:1 MANE Select	c.512C>T	p.Thr171Ile	missense	Exon 6 of 12	ENSP00000452762.1	P13804-1
	ETFA	ENST00000560595.6	TSL:1	c.512C>T	p.Thr171Ile	missense	Exon 6 of 14	ENSP00000453345.2	H0YLU7
	ETFA	ENST00000692691.1		c.512C>T	p.Thr171Ile	missense	Exon 6 of 13	ENSP00000508808.1	A0A8I5KVL5

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 9783 AN: 152150 Hom.: 433 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0422

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.0578

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0910

Gnomad OTH AF: 0.0569

GnomAD2 exomes AF: 0.0736 AC: 18483 AN: 251282 AF XY: 0.0757

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.0325

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.0552

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0907

Gnomad OTH exome AF: 0.0812

GnomAD4 exome AF: 0.0840 AC: 122594 AN: 1460138 Hom.: 5685 Cov.: 30 AF XY: 0.0837 AC XY: 60798 AN XY: 726474

African (AFR) AF: 0.0121 AC: 404 AN: 33474

American (AMR) AF: 0.0327 AC: 1464 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 956 AN: 26126

East Asian (EAS) AF: 0.0540 AC: 2144 AN: 39672

South Asian (SAS) AF: 0.0659 AC: 5677 AN: 86198

European-Finnish (FIN) AF: 0.130 AC: 6941 AN: 53412

Middle Eastern (MID) AF: 0.0479 AC: 276 AN: 5766

European-Non Finnish (NFE) AF: 0.0903 AC: 100237 AN: 1110436

Other (OTH) AF: 0.0745 AC: 4495 AN: 60340

GnomAD4 genome AF: 0.0643 AC: 9790 AN: 152270 Hom.: 433 Cov.: 32 AF XY: 0.0663 AC XY: 4933 AN XY: 74446

African (AFR) AF: 0.0155 AC: 643 AN: 41576

American (AMR) AF: 0.0422 AC: 645 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3472

East Asian (EAS) AF: 0.0571 AC: 296 AN: 5180

South Asian (SAS) AF: 0.0696 AC: 336 AN: 4830

European-Finnish (FIN) AF: 0.132 AC: 1399 AN: 10600

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0910 AC: 6188 AN: 68000

Other (OTH) AF: 0.0606 AC: 128 AN: 2112

Alfa AF: 0.0810 Hom.: 2226

Bravo AF: 0.0538

TwinsUK AF: 0.0920 AC: 341

ALSPAC AF: 0.0851 AC: 328

ESP6500AA AF: 0.0171 AC: 75

ESP6500EA AF: 0.0857 AC: 736

ExAC AF: 0.0761 AC: 9241

Asia WGS AF: 0.0720 AC: 253 AN: 3478

EpiCase AF: 0.0806

EpiControl AF: 0.0763

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Multiple acyl-CoA dehydrogenase deficiency (5)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0049	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.45
MPC		1.2
ClinPred		0.12	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.74
Mutation Taster		=255/45	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1801591; hg19: chr15-76578762; COSMIC: COSV51211583; COSMIC: COSV51211583;