chr19-51346976-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001985.3(ETFB):c.521G>A(p.Arg174His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,608,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R174C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

ETFB
NM_001985.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.04

Publications

1 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:

ENSG00000267984 (HGNC:):

ENSG00000267984 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.011149138).

BP6

Variant 19-51346976-C-T is Benign according to our data. Variant chr19-51346976-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 203699.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 = 0.00123 (187/152200) while in subpopulation AFR AF = 0.00438 (182/41506). AF 95% confidence interval is 0.00386. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETFB	NM_001985.3 link	c.521G>A	p.Arg174His	missense_variant	Exon 5 of 6	ENST00000309244.9	NP_001976.1	P38117-1
ETFB	NM_001014763.1 link	c.794G>A	p.Arg265His	missense_variant	Exon 4 of 5		NP_001014763.1	P38117-2
ETFB	XM_024451418.2 link	c.410G>A	p.Arg137His	missense_variant	Exon 5 of 6		XP_024307186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETFB	ENST00000309244.9 link	c.521G>A	p.Arg174His	missense_variant	Exon 5 of 6	1	NM_001985.3	ENSP00000311930.3		P38117-1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000371

AC:

AN:

240052

AF XY:

0.000354

show subpopulations

Gnomad AFR exome

AF:

0.00548

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000145

AC:

211

AN:

1456544

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

723944

show subpopulations

African (AFR)

AF:

0.00569

AC:

190

AN:

33372

American (AMR)

AF:

0.000159

AC:

AN:

44016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1109794

Other (OTH)

AF:

0.000150

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.00123

AC:

187

AN:

152200

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00438

AC:

182

AN:

41506

American (AMR)

AF:

0.000196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000450

Hom.:

Bravo

AF:

0.00130

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000379

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 07, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple acyl-CoA dehydrogenase deficiency

Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ETFB-related disorder

Benign:1

Feb 28, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

.;T;.

Eigen

Benign

-0.096

Eigen_PC

Benign

0.037

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.7

.;L;.

PhyloP100

2.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.0

N;N;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0080

D;D;.

Sift4G

Benign

0.11

T;T;.

Polyphen

0.57

P;B;.

Vest4

0.47

MVP

0.93

MPC

0.27

ClinPred

0.034

GERP RS

4.2

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.20

gMVP

0.56

Mutation Taster

=73/27

polymorphism

(source)

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

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