rs587777207
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001013703.4(EIF2AK4):c.3766C>T(p.Arg1256Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,824 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001013703.4 stop_gained
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 |
---|---|---|---|---|---|---|---|
EIF2AK4 | NM_001013703.4 | c.3766C>T | p.Arg1256Ter | stop_gained | 28/39 | ENST00000263791.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2AK4 | ENST00000263791.10 | c.3766C>T | p.Arg1256Ter | stop_gained | 28/39 | 2 | NM_001013703.4 | P1 | |
EIF2AK4 | ENST00000558629.5 | n.2683C>T | non_coding_transcript_exon_variant | 11/22 | 1 | ||||
EIF2AK4 | ENST00000560855.5 | c.3100C>T | p.Arg1034Ter | stop_gained | 23/34 | 5 | |||
EIF2AK4 | ENST00000558557.1 | n.923-600C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000922 AC: 23AN: 249412Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135308
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461720Hom.: 0 Cov.: 30 AF XY: 0.0000536 AC XY: 39AN XY: 727162
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74286
ClinVar
Submissions by phenotype
Familial pulmonary capillary hemangiomatosis Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 07, 2019 | The EIF2AK4 c.3766C>T; p.Arg1256Ter variant (rs587777207) is reported in the literature in multiple individuals affected with pulmonary capillary hemangiomatosis (Best 2014, Zhu 2018). In one family, this variant was observed in trans to a second pathogenic variant in two affected brothers and was absent from an unaffected sister, demonstrating co-segregation with disease (Best 2014). The p.Arg1256Ter variant is found in the non-Finnish European population with an overall allele frequency of 0.02% (21/113166 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Best DH et al. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest. 2014 Feb;145(2):231-236. Zhu N et al. Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults. Circ Genom Precis Med. 2018 Apr;11(4):e001887. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2021 | This sequence change creates a premature translational stop signal (p.Arg1256*) in the EIF2AK4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EIF2AK4 are known to be pathogenic (PMID: 12215525, 24135949, 24292273, 24310610, 28972005, 29743074). This variant is present in population databases (rs587777207, ExAC 0.03%). This premature translational stop signal has been observed in individual(s) with pulmonary capillary hemangiomatosis (PMID: 24135949). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 101528). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at