19-51345309-C-T

Position:

• chr19-51345309-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001985.3(ETFB):​c.670G>A​(p.Val224Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETFB NM_001985.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60

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]

ENSG00000267984 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3059234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETFB	NM_001985.3	c.670G>A	p.Val224Met	missense_variant	6/6	ENST00000309244.9	NP_001976.1
ETFB	NM_001014763.1	c.943G>A	p.Val315Met	missense_variant	5/5		NP_001014763.1
ETFB	XM_024451418.2	c.559G>A	p.Val187Met	missense_variant	6/6		XP_024307186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFB	ENST00000309244.9	c.670G>A	p.Val224Met	missense_variant	6/6	1	NM_001985.3	ENSP00000311930.3
ETFB	ENST00000354232.8	c.943G>A	p.Val315Met	missense_variant	5/5	1		ENSP00000346173.3
ETFB	ENST00000596253.1	c.511G>A	p.Val171Met	missense_variant	5/5	3		ENSP00000469628.1
ENSG00000267984	ENST00000600974.1	n.78+63C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2024

The c.670G>A (p.V224M) alteration is located in exon 6 (coding exon 6) of the ETFB gene. This alteration results from a G to A substitution at nucleotide position 670, causing the valine (V) at amino acid position 224 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		0.94	P;B;.
Vest4		0.43
MutPred		0.35		.;Loss of ubiquitination at K221 (P = 0.0609);.;
MVP		0.90
MPC		0.69
ClinPred		0.95	D
GERP RS		3.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.30
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51848563;