rs63751208

Variant names:

• chr11-5227172-G-A
• rs63751208
• ENST00000647020.1:c.-151C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-5227172-G-A
• chr11-5227172-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The ENST00000647020.1(HBB):​c.-151C>T variant causes a 5 prime UTR premature start codon gain 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: HBB ENST00000647020.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 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 Likely_pathogenic. Variant got 9 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 [Pathogenic]. Clinvar id is 15461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000647020.1	c.-151C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3			ENSP00000494175.1
HBB	ENST00000647020.1	c.-151C>T		5_prime_UTR_variant	Exon 1 of 3			ENSP00000494175.1
HBB	ENST00000380315.2	c.-18-133C>T		intron_variant	Intron 2 of 3	5		ENSP00000369671.2

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: Pathogenic

Submissions summary: Pathogenic:14 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:5 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 11, 2023

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 07, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 17, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Pathogenic:5

Sep 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Apr 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jun 18, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-151C>T variant (also known as -101C>T) has been reported in the homozygous and compound heterozygous state in individuals with beta-thalassemia intermedia (PMID: 30820323 (2019), 10606872 (1999), 2346726 (1990)). A functional study indicate this variant results in reduced HBB promoter activity (PMID: 2713503 (1989)). The frequency of this variant in the general population, 0.000032 (1/31400 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Mar 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Beta-thalassemia HBB/LCRB Pathogenic:1

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

HBB-related disorder Pathogenic:1

Dec 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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 Pathogenic:1

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beta-plus-thalassemia Pathogenic:1

Dec 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Malaria, susceptibility to Uncertain:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

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;