rs41417548
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000517.6(HBA2):c.314G>A(p.Cys105Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,220 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000517.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 25
GnomAD3 exomes AF: 0.0000202 AC: 5AN: 248070Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134572
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1458220Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 725242
GnomAD4 genome Cov.: 25
ClinVar
Submissions by phenotype
not provided Pathogenic:2
HBA2: PM3:Very Strong, PM2, PP1:Moderate, PS3:Supporting -
The Hb Sallanches variant (HBA2: c.314G>A; p.Cys105Tyr, also known as Cys104Tyr when numbered from the mature protein, rs41417548) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals with Hb H disease (Hb Var and references therein, Sharma 2020). Functional analyses show the variant protein is unstable and display a defect in binding with alpha-hemoglobin stabilizing protein (Sharma 2020, Wajcman 2011). This variant is reported in ClinVar (Variation ID: 15656). This variant is found in the South Asian population with an allele frequency of 0.017% (5/30278 alleles) in the Genome Aggregation Database. The cysteine at codon 105 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.678). Based on available information, this variant is considered to be likely pathogenic. References: Hb Var for Hb Sallanches: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=167&.cgifields=histD Sharma P et al. HbH disease due to compound heterozygosity for hemoglobins Zürich-Albisrieden and Sallanches. Pediatr Blood Cancer. 2020 Apr;67(4):e28161. PMID: 31930682. Wajcman H et al. a-Hemoglobin stabilizing protein: a modulating factor in thalassemias? Hemoglobin. 2011;35(5-6):463-8. PMID: 21950764. -
alpha Thalassemia Pathogenic:1
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with [GeneName] related disorder (ClinVar ID: VCV000015656, PMID:8555062). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10722113). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000804215, PMID:23181747). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.678>=0.6). A missense variant is a common mechanism . Itis observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000202). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Hemoglobin H disease, nondeletional Pathogenic:1
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alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 Pathogenic:1
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Hemoglobin H disease Pathogenic:1
This variant (also known as Hb Sallanches variant; Cys104Tyr) has been previously reported multiple individuals with Hemoglobin H disease in homozygous state [PMID: 11186268, 8555062, 10722113, 20113287]. Functional analyses showed the variant protein is unstable and display a defect in binding with alpha-hemoglobin stabilizing protein [31930682, 21950764]. -
HEMOGLOBIN SALLANCHES Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at