rs33927093
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000518.5(HBB):c.422C>T(p.Ala141Val) variant causes a missense 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A141T) has been classified as Pathogenic.
Frequency
Consequence
NM_000518.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.422C>T | p.Ala141Val | missense_variant | 3/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.422C>T | p.Ala141Val | missense_variant | 3/3 | 1 | NM_000518.5 | P1 | |
HBB | ENST00000647020.1 | c.422C>T | p.Ala141Val | missense_variant | 3/3 | P1 | |||
HBB | ENST00000633227.1 | c.*238C>T | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 3 | ||||
HBB | ENST00000475226.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hemoglobinopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2023 | Variant summary: HBB c.422C>T (p.Ala141Val), also known as Hb Puttelange, results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251376 control chromosomes (gnomAD). c.422C>T has been reported in the literature in multiple individuals affected with autosomal dominant erythrocytosis/polycythemia, including two de novo occurrences in siblings, in which the variant was suspected of occurring in the paternal germline (e.g., Wajcman_1995, Oliveira_2018). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant leads to increased oxygen affinity and reduced stability (e.g., Wajcman_1995). To our knowledge, this variant has not been reported in any individuals affected with autosomal recessive HBB-related disorders. The following publications have been ascertained in the context of this evaluation (PMID: 29790589, 15921161). One ClinVar submitter (evaluation after 2014) has cited the variant, but classified the variant as "other". Based on the evidence outlined above, the variant was classified as pathogenic. - |
HEMOGLOBIN PUTTELANGE Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at