GeneBe

chr11-5227127-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000647020.1(HBB):​c.-106G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

HBB
ENST00000647020.1 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.48

Publications

1 publications found
Variant links:
Genes affected
HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]
HBB Gene-Disease associations (from GenCC):
  • dominant beta-thalassemia
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
  • hemoglobin M disease
    Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
  • beta thalassemia
    Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
  • beta-thalassemia HBB/LCRB
    Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
  • sickle cell disease and related diseases
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • erythrocytosis, familial, 6
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • Heinz body anemia
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • sickle cell disease
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
  • hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • beta-thalassemia intermedia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • beta-thalassemia major
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • delta-beta-thalassemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin C disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin C-beta-thalassemia syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin E disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin E-beta-thalassemia syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-beta-thalassemia disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin c disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin d disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin E disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000647020.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
HBB
NM_000518.5
MANE Select
c.-106G>A
upstream_gene
N/ANP_000509.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
HBB
ENST00000647020.1
c.-106G>A
5_prime_UTR
Exon 1 of 3ENSP00000494175.1
HBB
ENST00000380315.2
TSL:5
c.-18-88G>A
intron
N/AENSP00000369671.2
ENSG00000298932
ENST00000759072.1
n.265+1399C>T
intron
N/A

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
8
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jun 13, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The HBB c.-106G>A variant is located in the 5'-untranslated region of the beta globin mRNA. To the best of our knowledge, this variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). A different nucleotide substitution at this position, c.-106G>C, has been reported in the homozygous state in an individual with minor beta(+)-thalassemia (PMID: 25754248 (2015)), but as a silent variant when in combination with Hb S or another beta(0)-thalassemia variant (PMID: 29157184 (2017)). Based on the available information, the c.-106G>A variant is classified as a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
CADD
Benign
14
DANN
Benign
0.78
PhyloP100
-1.5
PromoterAI
-0.076
Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs63750681; hg19: chr11-5248357; API