chr19-51354360-T-TG

Variant names:

• chr19-51354360-T-TG
• rs74357706
• ENST00000354232.8:c.278dupC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_001014763.1(ETFB):​c.278dupC​(p.Pro94ThrfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,613,884 control chromosomes in the GnomAD database, including 1,438 homozygotes. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.029 (103 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1335 hom.)
• Consequence: ETFB NM_001014763.1 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -3.08
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 19-51354360-T-TG is Benign according to our data. Variant chr19-51354360-T-TG is described in ClinVar as Benign. ClinVar VariationId is 203695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0294 (4476/152062) while in subpopulation NFE AF = 0.042 (2855/67942). AF 95% confidence interval is 0.0407. There are 103 homozygotes in GnomAd4. There are 2159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 103 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014763.1. 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.58-53dupC		intron	N/A	NP_001976.1
	ETFB	NM_001014763.1		c.278dupC	p.Pro94ThrfsTer8	frameshift	Exon 1 of 5	NP_001014763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFB	ENST00000354232.8	TSL:1	c.278dupC	p.Pro94ThrfsTer8	frameshift	Exon 1 of 5	ENSP00000346173.3
	ETFB	ENST00000309244.9	TSL:1 MANE Select	c.58-53dupC		intron	N/A	ENSP00000311930.3
	ENSG00000269403	ENST00000600067.1	TSL:5	n.116-53dupC		intron	N/A	ENSP00000469452.1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4475 AN: 151944 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00820

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.0675

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0401

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0420

Gnomad OTH AF: 0.0374

GnomAD2 exomes AF: 0.0340 AC: 8516 AN: 250442 AF XY: 0.0366

Gnomad AFR exome AF: 0.00616

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.0665

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0417

Gnomad OTH exome AF: 0.0353

GnomAD4 exome AF: 0.0392 AC: 57293 AN: 1461822 Hom.: 1335 Cov.: 33 AF XY: 0.0397 AC XY: 28902 AN XY: 727212

African (AFR) AF: 0.00672 AC: 225 AN: 33470

American (AMR) AF: 0.0234 AC: 1048 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 1765 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0457 AC: 3939 AN: 86258

European-Finnish (FIN) AF: 0.0296 AC: 1580 AN: 53382

Middle Eastern (MID) AF: 0.0517 AC: 298 AN: 5768

European-Non Finnish (NFE) AF: 0.0415 AC: 46141 AN: 1111994

Other (OTH) AF: 0.0379 AC: 2291 AN: 60392

GnomAD4 genome AF: 0.0294 AC: 4476 AN: 152062 Hom.: 103 Cov.: 32 AF XY: 0.0290 AC XY: 2159 AN XY: 74354

African (AFR) AF: 0.00817 AC: 339 AN: 41486

American (AMR) AF: 0.0283 AC: 433 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 234 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.0407 AC: 196 AN: 4814

European-Finnish (FIN) AF: 0.0285 AC: 302 AN: 10598

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0420 AC: 2855 AN: 67942

Other (OTH) AF: 0.0370 AC: 78 AN: 2106

Alfa AF: 0.0375 Hom.: 25

Bravo AF: 0.0281

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.0445

EpiControl AF: 0.0454

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	1	Multiple acyl-CoA dehydrogenase deficiency (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.1
Mutation Taster		=160/40	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74357706; hg19: chr19-51857614; COSMIC: COSV107361697; COSMIC: COSV107361697;