chr16-176718-T-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_000558.5(HBA1):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. 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
Consequence
NM_000558.5 start_lost
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBA1 | ENST00000320868.9 | c.2T>A | p.Met1? | start_lost | Exon 1 of 3 | 1 | NM_000558.5 | ENSP00000322421.5 | ||
HBA1 | ENST00000472694.1 | n.21T>A | non_coding_transcript_exon_variant | Exon 1 of 2 | 1 | |||||
HBA1 | ENST00000397797 | c.-46T>A | 5_prime_UTR_variant | Exon 1 of 3 | 2 | ENSP00000380899.1 | ||||
HBA1 | ENST00000487791.1 | n.-30T>A | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes Cov.: 28
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.88e-7 AC: 1AN: 1453242Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 722450
GnomAD4 genome Cov.: 28
ClinVar
Submissions by phenotype
alpha Thalassemia Pathogenic:1
Variant summary: HBA1 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met33) is located in the encoded protein. An activation of potential downstream translation at this initiation site would result in a shortened protein missing the first 32 amino acids from the protein sequence. At least one pathogenic missense variant has been reported upstream of this alternate codon in ClinVar. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230058 control chromosomes (gnomAD). c.2T>A has been reported in the literature as a homozygous and as a heterozygous genotype in individuals suspected of alpha thalassemia and in the heterozygous state in alpha thalassemia trait carriers presenting with mild microcytosis and hypochromia (e.g. Waye_2016, Keikhaei_2018). These reports do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, however another variant affecting the initiation codon (c.2T>G, p.Met1Arg) has been classified as pathogenic in ClinVar. The following publications have been ascertained in the context of this evaluation (PMID: 29627922, 28865746, 27821014). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at