chr11-5227158-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The ENST00000647020.1(HBB):​c.-137C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 554,166 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

HBB
ENST00000647020.1 5_prime_UTR

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 3.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5227158-G-C is Pathogenic according to our data. Variant chr11-5227158-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227158-G-C is described in Lovd as [Pathogenic]. Variant chr11-5227158-G-C is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.5). . 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
HBBENST00000647020.1 linkc.-137C>G 5_prime_UTR_variant Exon 1 of 3 ENSP00000494175.1 P68871
HBBENST00000380315.2 linkc.-18-119C>G intron_variant Intron 2 of 3 5 ENSP00000369671.2 F8W6P5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000198
AC:
11
AN:
554166
Hom.:
0
Cov.:
5
AF XY:
0.0000200
AC XY:
6
AN XY:
299838
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000576
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000281
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Feb 18, 2025
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, as transcient transfection of the gene with c.-137C>G in Hela cells showed reduction of beta-globin mRNA production (PMID: 6086605); Also known as -87C>G using alternate nomenclature; No data available from control populations to assess the frequency of this variant; Located in a regulatory region; This variant is associated with the following publications: (PMID: 2446680, 6188062, 22975760, 6280057, 7655036, 28503568, 2837728, 291719, 21228398, 31395865, 38927598, 37816374, 2375912, 35336809, 9163586, 7507641, 39359944, 38322302, 28385923, 36054783, 6086605, 27821015, 39859286, 20704537, 28399358) -

Nov 11, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HBB c.-137C>G variant (rs33941377, HbVar ID: 758), also known as -87 (C->G), is reported in the literature in multiple individuals affected with beta+ thalassemia (see HbVar database link and references therein, Orkin 1982). This variant is located in a conserved region of the beta globin gene promoter and functional analyses demonstrated a significant reduction in transcription (Treisman 1983). This variant is reported in ClinVar (Variation ID: 15464) and absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Orkin SH et al. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982 Apr 15;296(5858):627-31. PMID: 6280057. Treisman R et al. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591-6. PMID: 6188062. -

May 19, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HBB c.-137C>G pathogenic variant (also known as -87C>G) is located in the 5'-UTR of the HBB gene, and has been reported to deleteriously affected the promoter and transcription level of the beta-globin gene (PMIDs: 28503568 (2017), 2917193 (1989)). This variant is associated with beta(+)-thalassemia (PMIDs: 28503568 (2017), 21228398 (2011), 2917193 (1989), 2446680 (1988), 6280057 (1982)). Based on the available information, this variant is classified as pathogenic. -

Jul 13, 2023
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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects HBB function (PMID: 2837728, 6188062). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 15464). This variant is also known as -87C>G. This variant has been observed in individuals with beta-thalassemia (PMID: 2375912, 2446680, 2917193). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

beta Thalassemia Pathogenic:2Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Dec 19, 2019
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000518.4(HBB):c.-137C>G(aka -87C>G) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 2446680, 2375912, 2917193 and 2837728. Classification of NM_000518.4(HBB):c.-137C>G(aka -87C>G) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Mar 17, 2017
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

alpha Thalassemia;C0002895: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 06, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Beta thalassemia intermedia Pathogenic:1
Aug 18, 2011
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing;curation

- -

Beta-plus-thalassemia Pathogenic:1
Apr 15, 1982
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.50
CADD
Benign
16
DANN
Benign
0.67

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs33941377; hg19: chr11-5248388; API