19-51347006-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001985.3(ETFB):c.491G>A(p.Arg164Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,266 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164W) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: ETFB NM_001985.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-51347007-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1454900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 19-51347006-C-T is Pathogenic according to our data. Variant chr19-51347006-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETFB	NM_001985.3	c.491G>A	p.Arg164Gln	missense_variant	5/6	ENST00000309244.9
ETFB	NM_001014763.1	c.764G>A	p.Arg255Gln	missense_variant	4/5
ETFB	XM_024451418.2	c.380G>A	p.Arg127Gln	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETFB	ENST00000309244.9	c.491G>A	p.Arg164Gln	missense_variant	5/6	1	NM_001985.3	P1
	ENST00000600974.1	n.78+1760C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 247978 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134054

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 11, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 164 of the ETFB protein (p.Arg164Gln). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg164 amino acid residue in ETFB. Other variant(s) that disrupt this residue have been observed in individuals with ETFB-related conditions (PMID: 18289905, 27081516), which suggests that this may be a clinically significant amino acid residue. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ETFB protein function. ClinVar contains an entry for this variant (Variation ID: 16716). This variant is also known as c.518G>A and p.Arg174Gln. This missense change has been observed in individual(s) with glutaric acidemia type II (PMID: 7912128; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -

Glutaric acidemia IIb Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0090	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.89
MVP		0.96
MPC		0.44
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.95
gMVP		0.93

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: rs104894677; hg19: chr19-51850260; COSMIC: COSV100164357; COSMIC: COSV100164357;