rs1555691399
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The ENST00000340533.9(CYB5A):c.81G>A(p.Trp27Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
CYB5A
ENST00000340533.9 stop_gained
ENST00000340533.9 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.01
Genes affected
CYB5A (HGNC:2570): (cytochrome b5 type A) The protein encoded by this gene is a membrane-bound cytochrome that reduces ferric hemoglobin (methemoglobin) to ferrous hemoglobin, which is required for stearyl-CoA-desaturase activity. Defects in this gene are a cause of type IV hereditary methemoglobinemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.8 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-74291795-C-T is Pathogenic according to our data. Variant chr18-74291795-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 524200.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYB5A | NM_148923.4 | c.81G>A | p.Trp27Ter | stop_gained | 1/5 | ENST00000340533.9 | NP_683725.1 | |
CYB5A | NM_001190807.3 | c.81G>A | p.Trp27Ter | stop_gained | 1/4 | NP_001177736.1 | ||
CYB5A | NM_001914.4 | c.81G>A | p.Trp27Ter | stop_gained | 1/6 | NP_001905.1 | ||
CYB5A | XM_011525835.3 | c.81G>A | p.Trp27Ter | stop_gained | 1/4 | XP_011524137.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYB5A | ENST00000340533.9 | c.81G>A | p.Trp27Ter | stop_gained | 1/5 | 1 | NM_148923.4 | ENSP00000341625 | P1 | |
CYB5A | ENST00000494131.6 | c.81G>A | p.Trp27Ter | stop_gained | 1/6 | 1 | ENSP00000436461 | |||
CYB5A | ENST00000397914.4 | c.81G>A | p.Trp27Ter | stop_gained | 1/4 | 3 | ENSP00000381011 | |||
CYB5A | ENST00000583418.1 | n.163G>A | non_coding_transcript_exon_variant | 1/4 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Methemoglobinemia type 4 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 17, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | This variant is interpreted as Likely Pathogenic, for Methemoglobinemia and ambiguous genitalia, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at