rs144640661

Positions:

• chr19-51347050-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001985.3(ETFB):​c.447C>T​(p.Phe149=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,613,998 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (59 hom.)
• Consequence: ETFB NM_001985.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0760

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-51347050-G-A is Benign according to our data. Variant chr19-51347050-G-A is described in ClinVar as [Benign]. Clinvar id is 203698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.076 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0042 (639/152306) while in subpopulation EAS AF= 0.04 (207/5174). AF 95% confidence interval is 0.0355. There are 6 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETFB	NM_001985.3	c.447C>T	p.Phe149=	synonymous_variant	5/6	ENST00000309244.9	NP_001976.1
ETFB	NM_001014763.1	c.720C>T	p.Phe240=	synonymous_variant	4/5		NP_001014763.1
ETFB	XM_024451418.2	c.336C>T	p.Phe112=	synonymous_variant	5/6		XP_024307186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFB	ENST00000309244.9	c.447C>T	p.Phe149=	synonymous_variant	5/6	1	NM_001985.3	ENSP00000311930	P1
	ENST00000600974.1	n.78+1804G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 152188 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0399

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00769 AC: 1926 AN: 250364 Hom.: 28 AF XY: 0.00768 AC XY: 1040 AN XY: 135416

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0437

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.00587

Gnomad NFE exome AF: 0.000645

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00307 AC: 4486 AN: 1461692 Hom.: 59 Cov.: 34 AF XY: 0.00328 AC XY: 2384 AN XY: 727128

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0434

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.00478

Gnomad4 NFE exome AF: 0.000488

Gnomad4 OTH exome AF: 0.00513

GnomAD4 genome AF: 0.00420 AC: 639 AN: 152306 Hom.: 6 Cov.: 32 AF XY: 0.00496 AC XY: 369 AN XY: 74462

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0400

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00516

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 04, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs144640661; hg19: chr19-51850304; COSMIC: COSV58535436; COSMIC: COSV58535436;