chr19-51353280-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001985.3(ETFB):c.227G>A(p.Arg76His) variant causes a missense change. The variant allele was found at a frequency of 0.000134 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ETFB
NM_001985.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.79

Publications

6 publications found

Variant links:

Genes affected

ETFB (HGNC:3482): (electron transfer flavoprotein subunit beta) This gene encodes electron-transfer-flavoprotein, beta polypeptide, which shuttles electrons between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. The gene deficiencies have been implicated in type II glutaricaciduria. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

ETFB Gene-Disease associations (from GenCC):

multiple acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia

ETFB links:

ENSG00000269403 (HGNC:):

ENSG00000269403 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ETFB	NM_001985.3 link	c.227G>A	p.Arg76His	missense_variant	Exon 3 of 6	ENST00000309244.9	NP_001976.1
ETFB	NM_001014763.1 link	c.500G>A	p.Arg167His	missense_variant	Exon 2 of 5		NP_001014763.1
ETFB	XM_024451418.2 link	c.116G>A	p.Arg39His	missense_variant	Exon 3 of 6		XP_024307186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ETFB	ENST00000309244.9 link	c.227G>A	p.Arg76His	missense_variant	Exon 3 of 6	1	NM_001985.3	ENSP00000311930.3
ENSG00000269403	ENST00000600067.1 link	n.*153G>A		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000469452.1
ENSG00000269403	ENST00000600067.1 link	n.*153G>A		3_prime_UTR_variant	Exon 3 of 4	5		ENSP00000469452.1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000228

AC:

AN:

250230

AF XY:

0.000229

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000435

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461560

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000345

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000146

AC:

162

AN:

1111848

Other (OTH)

AF:

0.000182

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41406

American (AMR)

AF:

0.0000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000430

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.227G>A (p.R76H) alteration is located in exon 3 (coding exon 3) of the ETFB gene. This alteration results from a G to A substitution at nucleotide position 227, causing the arginine (R) at amino acid position 76 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Multiple acyl-CoA dehydrogenase deficiency

Uncertain:1

Jan 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 76 of the ETFB protein (p.Arg76His). This variant is present in population databases (rs148567433, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with ETFB-related conditions. ClinVar contains an entry for this variant (Variation ID: 203702). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ETFB protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

.;D

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.4

.;H

PhyloP100

6.8

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.88

MVP

0.98

MPC

0.89

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.9

Varity_R

0.92

gMVP

0.75

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over