rs149278633

Variant names:

• chr4-158682400-C-T
• rs149278633
• NM_004453.4:c.381C>T
• ETFDH p.Leu127Leu

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004453.4(ETFDH):​c.381C>T​(p.Leu127Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,613,988 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: ETFDH NM_004453.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.819
• Publications: 0 publications found

Genes affected

ETFDH (HGNC:3483): (electron transfer flavoprotein dehydrogenase) This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

ETFDH Gene-Disease associations (from GenCC):

• multiple acyl-CoA dehydrogenase deficiency

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 4-158682400-C-T is Benign according to our data. Variant chr4-158682400-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00326 (496/152236) while in subpopulation AFR AF = 0.0116 (480/41532). AF 95% confidence interval is 0.0107. There are 2 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004453.4. 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
	ETFDH	NM_004453.4	MANE Select	c.381C>T	p.Leu127Leu	synonymous	Exon 3 of 13	NP_004444.2	Q16134-1
	ETFDH	NM_001281737.2		c.240C>T	p.Leu80Leu	synonymous	Exon 2 of 12	NP_001268666.1	Q16134-3
	ETFDH	NM_001281738.1		c.198C>T	p.Leu66Leu	synonymous	Exon 1 of 11	NP_001268667.1	B4DEQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFDH	ENST00000511912.6	TSL:1 MANE Select	c.381C>T	p.Leu127Leu	synonymous	Exon 3 of 13	ENSP00000426638.1	Q16134-1
	ETFDH	ENST00000506422.1	TSL:1	n.86+9910C>T		intron	N/A
	ETFDH	ENST00000684622.1		c.381C>T	p.Leu127Leu	synonymous	Exon 3 of 14	ENSP00000507546.1	A0A804HJK8

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 152118 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000823 AC: 207 AN: 251382 AF XY: 0.000596

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000295 AC: 431 AN: 1461752 Hom.: 1 Cov.: 31 AF XY: 0.000261 AC XY: 190 AN XY: 727184

African (AFR) AF: 0.0110 AC: 368 AN: 33476

American (AMR) AF: 0.000403 AC: 18 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111900

Other (OTH) AF: 0.000629 AC: 38 AN: 60388

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152236 Hom.: 2 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74426

African (AFR) AF: 0.0116 AC: 480 AN: 41532

American (AMR) AF: 0.000916 AC: 14 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00351

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -17

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149278633;

hg19: chr4-159603552;