chr19-51354360-T-TG

Position:

• chr19-51354360-T-TG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The ENST00000354232.8(ETFB):​c.278_279insC​(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 ENST00000354232.8 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -3.08

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 103 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETFB	NM_001985.3	c.58-53_58-52insC		intron_variant		ENST00000309244.9	NP_001976.1
ETFB	NM_001014763.1	c.278_279insC	p.Pro94ThrfsTer8	frameshift_variant	1/5		NP_001014763.1
ETFB	XM_024451418.2	c.-54-53_-54-52insC		intron_variant			XP_024307186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFB	ENST00000354232.8	c.278_279insC	p.Pro94ThrfsTer8	frameshift_variant	1/5	1		ENSP00000346173
ETFB	ENST00000309244.9	c.58-53_58-52insC		intron_variant		1	NM_001985.3	ENSP00000311930	P1
ETFB	ENST00000596253.1	c.58-53_58-52insC		intron_variant		3		ENSP00000469628
ETFB	ENST00000593992.1	n.81-53_81-52insC		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.0340 AC: 8516 AN: 250442 Hom.: 205 AF XY: 0.0366 AC XY: 4956 AN XY: 135394

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 SAS exome AF: 0.0468

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

Gnomad4 AFR exome AF: 0.00672

Gnomad4 AMR exome AF: 0.0234

Gnomad4 ASJ exome AF: 0.0675

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0457

Gnomad4 FIN exome AF: 0.0296

Gnomad4 NFE exome AF: 0.0415

Gnomad4 OTH exome AF: 0.0379

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

Gnomad4 AFR AF: 0.00817

Gnomad4 AMR AF: 0.0283

Gnomad4 ASJ AF: 0.0675

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0407

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.0420

Gnomad4 OTH AF: 0.0370

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

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	South Asian population allele frequency is 4.479% (rs141529162, 1,433/30,614 alleles, 58 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.1.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 406/12518=3.24% -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs74357706; hg19: chr19-51857614;