rs104894678

Variant names:

• chr19-51350385-C-A
• rs104894678
• NM_001985.3:c.382G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-51350385-C-A
• chr19-51350385-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001985.3(ETFB):​c.382G>T​(p.Asp128Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,350,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D128N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ETFB NM_001985.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 0 publications found

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

ENSG00000269403 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-51350385-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16718.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001985.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFB	NM_001985.3	MANE Select	c.382G>T	p.Asp128Tyr	missense	Exon 4 of 6	NP_001976.1
	ETFB	NM_001014763.1		c.655G>T	p.Asp219Tyr	missense	Exon 3 of 5	NP_001014763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFB	ENST00000309244.9	TSL:1 MANE Select	c.382G>T	p.Asp128Tyr	missense	Exon 4 of 6	ENSP00000311930.3
	ETFB	ENST00000354232.8	TSL:1	c.655G>T	p.Asp219Tyr	missense	Exon 3 of 5	ENSP00000346173.3
	ENSG00000269403	ENST00000600067.1	TSL:5	n.*308G>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000469452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1350200 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 676680

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31384

American (AMR) AF: 0.00 AC: 0 AN: 43758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 39170

South Asian (SAS) AF: 0.00 AC: 0 AN: 82634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5538

European-Non Finnish (NFE) AF: 9.87e-7 AC: 1 AN: 1013194

Other (OTH) AF: 0.00 AC: 0 AN: 56694

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		2.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.92		Gain of catalytic residue at I127 (P = 0.0372)
MVP		0.99
MPC		0.84
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.97
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs104894678; hg19: chr19-51853639;