rs63751208

chr11-5227172-G-Achr11-5227172-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000647020.1(HBB):c.-151C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000957 in 689,530 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1 O:1
• Conservation: PhyloP100: 1.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5227172-G-A is Pathogenic according to our data. Variant chr11-5227172-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15461.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=10, Uncertain_significance=1}. Variant chr11-5227172-G-A is described in Lovd as [Pathogenic]. Variant chr11-5227172-G-A is described in Lovd as [Pathogenic]. Variant chr11-5227172-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000647020.1	c.-151C>T		5_prime_UTR_variant	1/3			P1
HBB	ENST00000380315.2	c.-18-133C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 56 AN: 537340 Hom.: 1 Cov.: 4 AF XY: 0.000124 AC XY: 36 AN XY: 290572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000292

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.000135

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:5 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Sep 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The c.-151C>T variant in HBB, also known as -101C>T, has been reported in the compound heterozygous state with a severe beta thalassemia variant in numerous individuals with a mild form of thalassemia intermedia. It is the most common silent beta-thalassemia variant among individuals of Mediterranean descent (Gonzalez-Redondo 1989 PMID: 2713503, Ristaldi 1990 PMID: 2346726, Rund 1997 PMID: 8980256, HbVar, Maragoudaki 1999 PMID: 10606872). It has also been reported in ClinVar (Variation ID 15461) and has been identified in 10/68034 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant occurs in the beta-globin promoter, and in vitro functional studies support an impact on promoter activity (Gonzalez-Redondo 1989 PMID: 2713503). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PS4, PM1. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2017	Variant summary: c.-151C>T affects a non-conserved nucleotide in the promoter of HBB gene. Mutation Taster predicts a damaging outcome for this variant. This prediction was confirmed by a CAT promoter activity assay showing that this variant decreased promoter activity by 70% (Gonzalez-Redondo_1989). This variant was found in 1/31016 control chromosomes at a frequency of 0.0000322, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant is a well-known pathogenic HBB variant and has been reported in more than thirty unrelated patients with b-thalassemia intermedia. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 17, 2014	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 04, 2020	The c.-151C>T variant (also known as -101(C>T)) is located 101-bp upstream of the transcription initiation site. It causes slightly decreased transcription of the beta-globin gene, and is associated with beta (+)-thalassemia. Approximately one-third of individuals heterozygous for this variant have normal hematologic findings, with the remainder having either a slightly reduced MCH, slightly elevated levels of Hb A2, or a slight globin imbalance (, PMID: 2713503 (1989), 2346726 (1990), 10606872 (1999)). -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 03, 2023	The HBB c.-151C>T variant (rs63751208, HbVar ID: 649), also known as -101C>T, is associated with silent beta thalassemia in heterozygous carriers and has been described in individuals with a mild form of thalassemia intermedia who were compound heterozygous with a severe beta thalassemia variant (Gonzalez-Redondo 1989, Ristaldi 1990, Rund 1997, see HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 15461). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in a conserved region of the beta globin gene promoter and is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Gonzalez-Redondo JM et al. A C----T substitution at nt--101 in a conserved DNA sequence of the promotor region of the beta-globin gene is associated with "silent" beta-thalassemia. Blood. 1989 May 1;73(6):1705-11. PMID: 2713503 Ristaldi MS et al. The C-T substitution in the distal CACCC box of the beta-globin gene promoter is a common cause of silent beta thalassaemia in the Italian population. Br J Haematol. 1990 Apr;74(4):480-6. PMID: 2346726 Rund D et al. Genetic analysis of beta-thalassemia intermedia in Israel: diversity of mechanisms and unpredictability of phenotype. Am J Hematol. 1997 Jan;54(1):16-22. PMID: 8980256 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2022	Published functional studies demonstrate a significant loss of function (Gonzalez-Redondo et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); Reported as the most common silent beta-thalassemia variant among individuals of Mediterranean background (Maragoudaki et al., 1999); This variant is associated with the following publications: (PMID: 2001456, 7683931, 2346726, 25910213, 2713503, 7909640, 26202972, 28385923, 31395865, 34426522, 10606872) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs63751208, gnomAD 0.007%). This variant has been observed in individuals with HBB-related conditions, usually co-occurring with another severe beta-thalassemia variant (PMID: 2001456, 2713503, 10606872). It has also been observed to segregate with disease in related individuals. Of note, one homozygous individual was reported with beta-thalassemia intermedia (PMID: 30820323). This variant is also known as -101C>T. Studies have shown that this variant alters HBB gene expression (PMID: 2713503). For these reasons, this variant has been classified as Pathogenic. -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

HBB-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

The HBB c.-151C>T variant is located in the 5' untranslated region. This variant, also referred to as c.-101C>T using legacy nomenclature, is predicted to disrupt the CACCC promoter motif and has been reported to be causative for Beta-Thalassemia in the presence of a second pathogenic allele (Gonzalez-Redondo et al. 1989. PubMed ID: 2713503; Rund et al. 1997. PubMed ID: 8980256; Ristaldi et al. 1999. PubMed ID: 10575515). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1999

- -

Malaria, susceptibility to Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	14
Dann	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs63751208; hg19: chr11-5248402;