Genetic Variant HBB:c.-136C>G (chr11-5227157-G-C) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

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

The ENST00000647020.1(HBB):c.-136C>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 0.0000054 in 555,416 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: 0.0000054 ( 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: 2.48

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:

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 11-5227157-G-C is Pathogenic according to our data. Variant chr11-5227157-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227157-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.-136C>G		upstream_gene_variant		ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.-136C>G		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000540

AC:

AN:

555416

Hom.:

Cov.:

AF XY:

0.00000998

AC XY:

AN XY:

300506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000484

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Apr 29, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in presumably healthy individuals tested at GeneDx; Also known as -86C>G; This variant is associated with the following publications: (PMID: 2197725, 2393018, 26202972, 31395865, 1550780, 28385923, 23637309, 30173596, 22563936, 26291972, 1517101) -

Nov 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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 not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal recessive beta thalassemia intermedia (PMID: 1550780, 30173596). This variant is also known as c.-86C>G. ClinVar contains an entry for this variant (Variation ID: 15465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aug 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-136C>G variant (rs33994806, HbVar ID: 761), also known as -86 (C>G), has been reported in multiple homozygous individuals affected with beta(+)-thalassemia, as well as heterozygous individuals with beta-thalassemia trait (Bravo-Urquiola, 2012, He 2015, Moassas 2018, Thein 1990, HbVar database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in the functionally important proximal CACCC box in the HBB promoter, and variants in this promoter element are known to be associated with beta(+) thalassemia (Ropero 2017, Thein 2013). Based on available information, the c.-136C>G variant is considered to be pathogenic. References: HbVar database link: https://globin.bx.psu.edu/hbvar/menu.html Bravo-Urquiola M et al. Molecular spectrum of beta-thalassemia mutations in the admixed Venezuelan population, and their linkage to beta-globin gene haplotypes. Hemoglobin. 2012;36(3):209-18. PMID: 22563936. He S et al. First Description of a beta-Thalassemia Mutation, -86 (C>G) (HBB: c.-136C>G), in a Chinese Family. Hemoglobin. 2015;39(6):448-50. PMID: 26291972 Moassas F et al. Description of a Rare beta-Globin Gene Mutation: -86 (C>G) (HBB: c.-136C>G) Observed in a Syrian Family. Hemoglobin. 2018 May;42(3):203-205. PMID: 30173596. Ropero P et al. Phenotype of mutations in the promoter region of the beta-globin gene. J Clin Pathol. 2017 Oct;70(10):874-878. PMID: 28385923. Thein SL. The molecular basis of beta-thalassemia. Cold Spring Harb Perspect Med. 2013 May 1;3(5):a011700. PMID: 23637309. Thein SL et al. The molecular basis of beta-thalassemia in Thailand: application to prenatal diagnosis. Am J Hum Genet. 1990 Sep;47(3):369-75. PMID: 2393018. -

Apr 25, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-136C>G variant (also known as -86C>G) is located in an important region in the promoter of the beta-globin gene and is expected to cause decreased transcription. This variant is associated with mild beta(+)-thalassemia (PMIDs: 2197725 (1990), 2393018 (1990), 22563936 (2012), 26291972 (2015), 30173596 (2018)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

beta Thalassemia

Pathogenic:3Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Apr 03, 2015

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2024

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Beta-thalassemia HBB/LCRB

Pathogenic:1

May 07, 2024

MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBB c.-136C>G is a beta+ type of mutation located in the promoter of beta globin gene. When this variant present with other pathogenic HBB mutation leads to severe type of thalassemia. Patients needing blood transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 0.09 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations, Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018] -

Beta-plus-thalassemia

Pathogenic:1

Jun 01, 1992

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

-0.59

CADD

Benign

DANN

Benign

0.73

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