rs200186078

Positions:

• chr19-51346920-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP3 BP4_Strong BP6

The NM_001985.3(ETFB):​c.577G>A​(p.Ala193Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,560,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: ETFB NM_001985.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.16

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.020046145).
• BP6: Variant 19-51346920-C-T is Benign according to our data. Variant chr19-51346920-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 459959.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETFB	NM_001985.3	c.577G>A	p.Ala193Thr	missense_variant	5/6	ENST00000309244.9	NP_001976.1
ETFB	NM_001014763.1	c.850G>A	p.Ala284Thr	missense_variant	4/5		NP_001014763.1
ETFB	XM_024451418.2	c.466G>A	p.Ala156Thr	missense_variant	5/6		XP_024307186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFB	ENST00000309244.9	c.577G>A	p.Ala193Thr	missense_variant	5/6	1	NM_001985.3	ENSP00000311930.3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000220 AC: 37 AN: 168310 Hom.: 0 AF XY: 0.000224 AC XY: 20 AN XY: 89322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000194

Gnomad ASJ exome AF: 0.00255

Gnomad EAS exome AF: 0.000408

Gnomad SAS exome AF: 0.0000422

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000215

GnomAD4 exome AF: 0.0000966 AC: 136 AN: 1408228 Hom.: 0 Cov.: 30 AF XY: 0.0000934 AC XY: 65 AN XY: 695636

Gnomad4 AFR exome AF: 0.0000934

Gnomad4 AMR exome AF: 0.000191

Gnomad4 ASJ exome AF: 0.00289

Gnomad4 EAS exome AF: 0.000275

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.000240

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74482

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000110 AC: 13

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 08, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0060	D;D;.
Sift4G	Uncertain	0.033	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.86
MVP		0.96
MPC		0.58
ClinPred		0.37	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.86
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs200186078; hg19: chr19-51850174; COSMIC: COSV104618926; COSMIC: COSV104618926;