11-5227158-G-C

Position:

• chr11-5227158-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.-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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 3.42

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 11-5227158-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/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000647020.1	c.-137C>G		5_prime_UTR_variant	1/3			ENSP00000494175	P1
HBB	ENST00000380315.2	c.-18-119C>G		intron_variant		5		ENSP00000369671

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

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:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 05, 2023	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	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2023	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). 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. -
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	GeneDx	Oct 21, 2019	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 (Orkin et al., 1984); Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar SCV000939590.1; Landrum et al., 2016); Also known as -87C>G using alternate nomenclature; This variant is associated with the following publications: (PMID: 9163586, 31395865, 21228398, 291719, 2837728, 28503568, 7507641, 6086605, 7655036, 2446680, 6280057, 22975760, 6188062, 2375912) -

beta Thalassemia Pathogenic:2 Other: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	16
DANN	Benign	0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs33941377; hg19: chr11-5248388;