chr4-158706693-T-C

Position:

• chr4-158706693-T-C

Variant summary

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

The NM_004453.4(ETFDH):​c.1533T>C​(p.Asp511=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,614,166 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (58 hom.)
• Consequence: ETFDH NM_004453.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.134

Genes affected

ETFDH (HGNC:3483): (electron transfer flavoprotein dehydrogenase) This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-158706693-T-C is Benign according to our data. Variant chr4-158706693-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 137235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.134 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00532 (811/152330) while in subpopulation NFE AF= 0.00541 (368/68030). AF 95% confidence interval is 0.00495. There are 7 homozygotes in gnomad4. There are 481 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETFDH	NM_004453.4	c.1533T>C	p.Asp511=	synonymous_variant	12/13	ENST00000511912.6
ETFDH	NM_001281737.2	c.1392T>C	p.Asp464=	synonymous_variant	11/12
ETFDH	NM_001281738.1	c.1350T>C	p.Asp450=	synonymous_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETFDH	ENST00000511912.6	c.1533T>C	p.Asp511=	synonymous_variant	12/13	1	NM_004453.4	P1

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152212 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00657 AC: 1653 AN: 251440 Hom.: 21 AF XY: 0.00673 AC XY: 914 AN XY: 135888

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00359

Gnomad FIN exome AF: 0.0318

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00608 AC: 8894 AN: 1461836 Hom.: 58 Cov.: 31 AF XY: 0.00592 AC XY: 4307 AN XY: 727224

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00478

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00329

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.00575

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.00532 AC: 811 AN: 152330 Hom.: 7 Cov.: 32 AF XY: 0.00646 AC XY: 481 AN XY: 74502

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.0329

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00523 Hom.: 4

Bravo AF: 0.00307

EpiCase AF: 0.00469

EpiControl AF: 0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ETFDH: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 17, 2013

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	-0.52
CADD	Benign	0.97
DANN	Benign	0.60

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: rs77484245; hg19: chr4-159627845;