Variant chr11-5227158-G-C details in Genebe, Genetics Data Aggregator

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

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]

HBB links:

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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
HBB	ENST00000647020.1 link	c.-137C>G		5_prime_UTR_variant	Exon 1 of 3			ENSP00000494175.1		P68871
HBB	ENST00000380315.2 link	c.-18-119C>G		intron_variant	Intron 2 of 3	5		ENSP00000369671.2		F8W6P5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000198

AC:

AN:

554166

Hom.:

Cov.:

AF XY:

0.0000200

AC XY:

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.:

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

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2025	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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 19, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2023	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

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Beta thalassemia intermedia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;curation

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

Aug 18, 2011

- -

Beta-plus-thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 1982

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over