rs63750681

Variant names:

• chr11-5227127-C-G
• rs63750681
• ENST00000647020.1:c.-106G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-5227127-C-G
• chr11-5227127-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000647020.1(HBB):​c.-106G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 812,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:9
• Conservation: PhyloP100: -1.48
• Publications: 3 publications found

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

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.-106G>C		upstream_gene_variant		ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.-106G>C		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000300 AC: 198 AN: 659788 Hom.: 0 Cov.: 8 AF XY: 0.000286 AC XY: 101 AN XY: 353240

African (AFR) AF: 0.000167 AC: 3 AN: 17924

American (AMR) AF: 0.000297 AC: 11 AN: 36986

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 52 AN: 20594

East Asian (EAS) AF: 0.00 AC: 0 AN: 34394

South Asian (SAS) AF: 0.00 AC: 0 AN: 66572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44964

Middle Eastern (MID) AF: 0.00131 AC: 4 AN: 3056

European-Non Finnish (NFE) AF: 0.000237 AC: 95 AN: 401270

Other (OTH) AF: 0.000970 AC: 33 AN: 34028

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74476

African (AFR) AF: 0.0000722 AC: 3 AN: 41570

American (AMR) AF: 0.000719 AC: 11 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000370

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Sep 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-106G>C variant (rs63750681, HbVar ID: 2601, ClinVar Variation ID: 36281), also known as -56 (G>C), has been reported with a pathogenic beta globin variant in a patient with beta thalassemia intermedia (Agouti 2008) and in a patient with beta thalassemia minor (Belmokhtar 2022). Although the study suggested that the two variants are in-trans, parental samples were not available to confirm phase (Agouti 2008, Belmokhtar 2022). The c.-106G>C variant has also been reported homozygous in an individual presenting with minor B+-thalassemia with moderate microcytic anemia and low mean corpuscular hemoglobin concentration (Douzi 2015). More recently, the c.-106G>C variant was described in 10 individuals, eight heterozygotes with normal hematological and electrophoretic values, one individual who also carried Hb S with an indistinguishable phenotype from just Hb S carriers, and one individual compound heterozygous with a beta(0) variant and anti3.7 alpha globin rearrangement (Vinciguerra 2018). The authors concluded that the c.-106G>C variant is a rare benign variant (Vinciguerra 2018). This variant is found in the general population with a low overall allele frequency of 0.04% (11/31394 alleles) in the Genome Aggregation Database (v2.1.1). The variant is located in a weakly conserved nucleotide in the promoter region of beta globin that has not been previously associated with a molecular function, but a potential mild impact could not be excluded. Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES HbVar Database: https://globin.bx.psu.edu/hbvar/menu.html Agouti I et al. Beta-thalassemia intermedia due to two novel mutations in the promoter region of the beta-globin gene. Eur J Haematol. 2008 Apr;80(4):346-50. PMID: 18081706. Belmokhtar I et al. Molecular heterogeneity of ß-thalassemia variants in the Eastern region of Morocco. Mol Genet Genomic Med. 2022 Aug;10(8):e1970. PMID: 35615994. Douzi K et al. Two new beta+ -thalassemia mutation (B -56 (G ? C); HBBc. -106 G ? C) and (B -83 (G ? A); HBBc. -133 G ? A) described among the Tunisian population. Am J Hum Biol. 2015 Sep-Oct;27(5):716-9. PMID: 25754248. Vinciguerra M et al. Co-inheritance of HBB:c.-106G > C, a rare single nucleotide variation at position -56 relative to transcription initiation site, with other known mutations in the globin clusters. Hematology. 2018 Jul;23(6):368-372. PMID: 29157184

Mar 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-106G>C variant has been reported in the published literature in individuals with mild beta-thalassemia in the homozygous state or compound heterozygous state with the HBB c.92+1G>A beta(0)-thalassemia mutation (PMID: 18081706 (2008), 25754248 (2015)). More recent studies have characterized the variant as a benign variant or a silent mutation. It was observed in multiple heterozygous carriers with normal/borderline red cell indices and morphology, and compound heterozygosity with other globin mutations did not affect or worsen the phenotype (PMID: 29157184 (2017), 35615994 (2022)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect HBB mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.

Feb 22, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in apparent homozygous state in a patient with moderate microcytic anemia in the literature (PMID: 25754248); Also known as -56C>G; This variant is associated with the following publications: (PMID: 35615994, 29157184, 18081706, 25754248)

Jan 18, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

beta Thalassemia Pathogenic:1 Uncertain:1

Apr 23, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

not specified Uncertain:1

Sep 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.-106G>C is located in the untranscribed region upstream of the HBB gene region. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00031 in 812098 control chromosomes (gnomAD database v4). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia Intermedia (0.00031 vs 0.011), allowing no conclusion about variant significance. c.-106G>C, has been reported in the literature in a compound heterozygous patient together with a beta thalassemia major disease variant (c.92+1G>A), who had a beta thalassemia intermedia phenotype (Agouti_2008). The variant was also found in a homozygous individual, who displayed some features resembling to beta thalassemia minor, i.e. mild microcytic anemia, with low mean corpuscular hemoglobin concentration (Douzi_2015). These reports suggest that the variant might cause a milder phenotype, possibly affecting the beta gene expression. However, the variant was also reported in eight heterozygous individuals showing normal hematological values (i.e. being impossible to distinguish it from healthy, non-carrier subjects), and in at least three compound heterozygote patients carrying other globin disease variants, who showed phenotypes equivalent to patients carrying only the other alleles (Vinciguerra_2018, Belmokhtar_2022); therefore, these data suggest a benign role for the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18081706, 25754248, 21423179, 27718361, 26076395, 29157184, 35615994). ClinVar contains an entry for this variant (Variation ID: 36281). Based on the evidence outlined above, the variant was classified as uncertain significance.

Beta-thalassemia HBB/LCRB Uncertain:1

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Uncertain:1

Mar 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hb SS disease Uncertain:1

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.75
PhyloP100		-1.5
PromoterAI		-0.074	Neutral
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs63750681; hg19: chr11-5248357;