NM_004453.4:c.2T>C

Variant names:

• chr4-158672458-T-C
• rs121964953
• NM_004453.4:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004453.4(ETFDH):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ETFDH NM_004453.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.32

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]

C4orf46 (HGNC:27320): (chromosome 4 open reading frame 46) This gene encodes a small, conserved protein of unknown function that is expressed in a variety of tissues. There are pseudogenes for this gene on chromosomes 6, 8, 16, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 62 codons. Genomic position: 158682203. Lost 0.099 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-158672458-T-C is Pathogenic according to our data. Variant chr4-158672458-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12026.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETFDH	NM_004453.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 13	ENST00000511912.6	NP_004444.2
ETFDH	NM_001281737.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 12		NP_001268666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETFDH	ENST00000511912.6	c.2T>C	p.Met1?	start_lost	Exon 1 of 13	1	NM_004453.4	ENSP00000426638.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glutaric acidemia IIc Pathogenic:1

May 25, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:1

Apr 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ETFDH protein in which other variant(s) (p.Pro27Ser) have been determined to be pathogenic (PMID: 3126856, 20023066, 27038534; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 12026). Disruption of the initiator codon has been observed in individuals with multiple acyl-CoA dehydrogenase deficiency (PMID: 24357026, 29336361). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ETFDH mRNA. The next in-frame methionine is located at codon 62. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.13	.;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.0	D;N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		0.0	.;B;.
Vest4		0.89, 0.82
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0118);Gain of catalytic residue at M1 (P = 0.0118);Gain of catalytic residue at M1 (P = 0.0118);
MVP		0.95
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91
gMVP		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: rs121964953; hg19: chr4-159593610;