rs796051964
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004453.4(ETFDH):c.51dup(p.Ala18CysfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,605,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H17H) has been classified as Likely benign.
Frequency
Consequence
NM_004453.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ETFDH | NM_004453.4 | c.51dup | p.Ala18CysfsTer5 | frameshift_variant | 2/13 | ENST00000511912.6 | |
ETFDH | NM_001281737.2 | c.35-1712dup | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ETFDH | ENST00000511912.6 | c.51dup | p.Ala18CysfsTer5 | frameshift_variant | 2/13 | 1 | NM_004453.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152190Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000717 AC: 18AN: 250878Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135642
GnomAD4 exome AF: 0.000216 AC: 314AN: 1453688Hom.: 0 Cov.: 27 AF XY: 0.000210 AC XY: 152AN XY: 723690
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152190Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74360
ClinVar
Submissions by phenotype
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0202 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein but is located in an exon that may undergo alternative splicing. This variant is in exon 2 of 13 in the ETFDH gene. (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (20 Heterozygotes, 0 Homozygotes). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple (>5) NMD-predicted variants are present along the ETFDH gene (Decipher, ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with multiple acyl-CoA dehydrogenase deficiency (PMIDs: 12359134; 12815589; 17584774; 28468868). (P) 0905 - No segregation evidence has been identified for this variant in the literature. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change creates a premature translational stop signal (p.Ala18Cysfs*5) in the ETFDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ETFDH are known to be pathogenic (PMID: 16510302, 23785301). This variant is present in population databases (rs773961946, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ETFDH-related conditions (PMID: 12359134, 12815589, 17584774). ClinVar contains an entry for this variant (Variation ID: 195222). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 23, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 29, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 18, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12815589, 12359134, 17584774, 31268564) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at