rs761854400

Variant names:

• chr4-158697568-A-G
• rs761854400
• NM_004453.4:c.841A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-158697568-A-G
• chr4-158697568-A-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_004453.4(ETFDH):​c.841A>G​(p.Ile281Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000996 in 1,607,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I281F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ETFDH NM_004453.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.88
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.39306 (below the threshold of 3.09). Trascript score misZ: 0.49505 (below the threshold of 3.09). GenCC associations: The gene is linked to multiple acyl-CoA dehydrogenase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15948334).

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.841A>G	p.Ile281Val	missense	Exon 8 of 13	NP_004444.2	Q16134-1
	ETFDH	NM_001281737.2		c.700A>G	p.Ile234Val	missense	Exon 7 of 12	NP_001268666.1	Q16134-3
	ETFDH	NM_001281738.1		c.658A>G	p.Ile220Val	missense	Exon 6 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.841A>G	p.Ile281Val	missense	Exon 8 of 13	ENSP00000426638.1	Q16134-1
	ETFDH	ENST00000506422.1	TSL:1	n.87-5855A>G		intron	N/A
	ETFDH	ENST00000682734.1		c.-333A>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 10	ENSP00000507860.1	A0A804HKB8

Frequencies

GnomAD3 genomes AF: 0.0000470 AC: 7 AN: 149022 Hom.: 0 Cov.: 32

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: 0.000104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000921 AC: 23 AN: 249800 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1458074 Hom.: 0 Cov.: 33 AF XY: 0.0000979 AC XY: 71 AN XY: 725378

African (AFR) AF: 0.0000599 AC: 2 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52018

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5676

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1110478

Other (OTH) AF: 0.000133 AC: 8 AN: 60274

GnomAD4 genome AF: 0.0000470 AC: 7 AN: 149022 Hom.: 0 Cov.: 32 AF XY: 0.0000414 AC XY: 3 AN XY: 72520

African (AFR) AF: 0.00 AC: 0 AN: 40412

American (AMR) AF: 0.00 AC: 0 AN: 14872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67374

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Multiple acyl-CoA dehydrogenase deficiency (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.071	D
MutationAssessor	Benign	0.34	N
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.27
Sift	Benign	0.59	T
Sift4G	Benign	0.86	T
Polyphen		0.011	B
Vest4		0.38
MVP		0.90
MPC		0.081
ClinPred		0.076	T
GERP RS		5.5
Varity_R		0.096
gMVP		0.56
Mutation Taster		=84/16	polymorphism

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: rs761854400; hg19: chr4-159618720;