rs794728013
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000398.7(CYB5R3):c.464-2A>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,610,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000398.7 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYB5R3 | NM_000398.7 | c.464-2A>C | splice_acceptor_variant | ENST00000352397.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYB5R3 | ENST00000352397.10 | c.464-2A>C | splice_acceptor_variant | 1 | NM_000398.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 151992Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251442Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
GnomAD4 exome AF: 0.00000549 AC: 8AN: 1458058Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 725664
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 151992Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74264
ClinVar
Submissions by phenotype
Deficiency of cytochrome-b5 reductase Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 05, 2022 | ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2018 | This variant has been observed in individuals affected with recessive congenital methemoglobinemia (RCM) type II (PMID: 15921385, 9266404). ClinVar contains an entry for this variant (Variation ID: 245). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CYB5R3 are known to be pathogenic (PMID: 18318771). Experimental studies have shown that this intronic change causes aberrant splicing of the CYB5R3 mRNA (PMID: 9266404). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 5 of the CYB5R3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2022 | Canonical splice site variant expected to result in aberrant splicing, and in vitro studies demonstrate altered splicing (Maran et al., 2005); This variant is associated with the following publications: (PMID: 31898843, 25525159, 15921385, 15744830, 9266404) - |
Methemoglobinemia type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2005 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at