Variant 11-5227158-G-A 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>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 0.00000991 in 706,420 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: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

HBB
ENST00000647020.1 5_prime_UTR

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O: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-A is Pathogenic according to our data. Variant chr11-5227158-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227158-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43). . 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>T		5_prime_UTR_variant	Exon 1 of 3			ENSP00000494175.1		P68871
HBB	ENST00000380315.2 link	c.-18-119C>T		intron_variant	Intron 2 of 3	5		ENSP00000369671.2		F8W6P5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000902

AC:

AN:

554166

Hom.:

Cov.:

AF XY:

0.0000100

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:

0.00000938

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 2018842, 20524821, 27821015). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -87C>T. ClinVar contains an entry for this variant (Variation ID: 36287). Studies have shown that this variant alters HBB gene expression (PMID: 2018842). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2023	Published functional studies demonstrate a damaging effect, as transfection of the gene with c.-137C>T in HeLa cells showed a reduction of beta globin gene transcriptional activity (Kulozik et al., 1991; Kircher et al., 2019); Also known as -87C>T; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 11857746, 2018842, 20524821, 31395865, 27821015, 9163586, 21119755, 21423179, 1550780) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 05, 2024	The HBB c.-137C>T variant (rs33941377, HbVarID: 759), also known as -87C>T, is reported in the literature in several individuals with beta thalassemia intermedia, both of whom carried an additional pathogenic variant (Kulozik 1991, Gallagher 2016, HbVar database). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in HBB promoter in the CACCC box that promotes gene transcription, and functional assays indicate that this variant results in reduced transcriptional activity (Kulozik 1991). Based on available information, this variant is considered pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Gallagher PG et al. Mutation in a Highly Conserved COOH-Terminal Residue of Kruppel-Like Factor 1 Associated with Elevated Hb F in a Compound Heterozygous beta-Thalassemia Patient with a Nontransfusion-Dependent Thalassemia Phenotype. Hemoglobin. 2016 Sep;40(5):361-364. PMID: 27821015. Kulozik AE et al. Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element. Blood. 1991 May 1;77(9):2054-8. PMID: 2018842. -

Beta thalassemia intermedia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 30, 2023

Variant summary: HBB c.-137C>T is located in the untranscribed region upstream of the HBB gene region. The variant was absent in 31398 control chromosomes. Ithanet lists this variant in association with + phenotype with relative carrier frequencies as follow: Czech Republic 2%, Slovakia 2%, Germany 1%, United Kingdom 0.2%, Italy 0.1%, and India 0.04%. The variant was found in multiple patients with symptoms ranging from beta-thalassemia major to beta-thalassemia intermedia depending on the second variant in trans and/or presence of alteration in genes encoding a-chain. Functional studies have shown that this variant leads to reduced transcription rate and synthesis of HBB (Kulozik_1991). The following publications have been ascertained in the context of this evaluation (PMID: 2018842, 11857746, 21119755, 21423179, 20524821, 27821015, 1550780). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 04, 2024

- -

Hb SS disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

beta Thalassemia

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

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