ENST00000647020.1:c.-78A>C

Variant names:

• chr11-5227099-T-G
• rs33931746
• ENST00000647020.1:c.-78A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The ENST00000647020.1(HBB):​c.-78A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 865,286 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.34
• Publications: 92 publications found

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 Gene-Disease associations (from GenCC):

• dominant beta-thalassemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia intermedia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia major

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-beta-thalassemia disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin c disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin d disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin E disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5227099-T-G is Pathogenic according to our data. Variant chr11-5227099-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 15470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000647020.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.-78A>C		upstream_gene	N/A	NP_000509.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	ENST00000647020.1		c.-78A>C		5_prime_UTR	Exon 1 of 3	ENSP00000494175.1
	HBB	ENST00000380315.2	TSL:5	c.-18-60A>C		intron	N/A	ENSP00000369671.2
	ENSG00000298932	ENST00000759072.1		n.265+1371T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000347 AC: 3 AN: 865286 Hom.: 0 Cov.: 12 AF XY: 0.00000220 AC XY: 1 AN XY: 453722

African (AFR) AF: 0.00 AC: 0 AN: 21842

American (AMR) AF: 0.00 AC: 0 AN: 42200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22232

East Asian (EAS) AF: 0.00 AC: 0 AN: 37034

South Asian (SAS) AF: 0.00 AC: 0 AN: 73830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51330

Middle Eastern (MID) AF: 0.000486 AC: 2 AN: 4116

European-Non Finnish (NFE) AF: 0.00000175 AC: 1 AN: 571906

Other (OTH) AF: 0.00 AC: 0 AN: 40796

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000308 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:3

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

Mar 10, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The HBB c.-78A>C variant involves the alteration of a non-conserved nucleotide in the promoter region (transcriptional TATA box). One in silico tool predicts a damaging outcome for this variant. The variant of interest was observed in controls with an allele frequency of 0.0000322 (1/31018), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in multiple BTHAL-ITMD cases both as homozygotes and compound heterozygotes. In addition, multiple reputable databases classified this variant as pathogenic. Furthermore, another variant at this location, c.-78A>G has been reported and classified by LCA as "pathogenic," supporting the importance of this region/location for proper function. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Pathogenic."

Nov 06, 2018

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:3

Feb 16, 2024

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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive HBB-related disease (PMID: 2200760, 8619407, 16103715, 17994378, 19960060). 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 -28 A>C. ClinVar contains an entry for this variant (Variation ID: 15470). Studies have shown that this variant alters HBB gene expression (PMID: 2987224, 24616209). For these reasons, this variant has been classified as Pathogenic.

Feb 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-78A>C variant (rs33931746, HbVar ID: 768), also known as -28 (A>C), is reported in the literature in individuals affected with beta (+) thalassemia (Agouti 2008, Gamarra 2009, Perea 1996, Poncz 1982, HbVar database) or in heterozygous carriers with microcytic anemia (Gamarra 2009, Perea 1996). In several individuals with beta thalassemia major, this variant was observed in trans to a beta-0 pathogenic variant (Gamarra 2009, Perea 1996). The c.-78A>C variant is located in the TATA box of the HBB gene (Poncz 1982), and functional analyses in transfected HeLa cells suggest it leads to a 2- to 3-fold decrease in beta globin transcription (Surrey 1985). Another variant at this position, c.-78A>G, is a common beta+ pathogenic variant that leads to a 3- to 5-fold reduction in HBB transcripts (Orkin 1983, Yamsri 2011). The c.-78A>C variant is 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: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Agouti I et al. Molecular basis of beta-thalassemia in Morocco: possible origins of the molecular heterogeneity. Genet Test. 2008 Dec;12(4):563-8. PMID: 18976160. Gamarra S et al. beta-Thalassaemia Major in a Spanish Patient due to a Compound Heterozygosity for CD39 C > T/-28 A > C. Adv Hematol. 2009;2009:476342. PMID: 19960060. Orkin SH et al. ATA box transcription mutation in beta-thalassemia. Nucleic Acids Res. 1983; 11(14):4727-34. PMID: 6308558. Perea FJ et al. Haplotype analysis of the Mexican frameshift Cd 11 (-T) and -28 A->C beta-thalassemia alleles. Am J Hematol. 1996 Mar;51(3):240-2. PMID: 8619407. Poncz M et al. beta-Thalassemia in a Kurdish Jew. Single base changes in the T-A-T-A box. J Biol Chem. 1982 Jun 10;257(11):5994-6. PMID: 7076659. Surrey S et al. Functional analysis of a beta-globin gene containing a TATA box mutation from a Kurdish Jew with beta thalassemia. J Biol Chem. 1985 Jun 10;260(11):6507-10. PMID: 2987224. Yamsri S et al. Genotype and phenotype characterizations in a large cohort of beta-thalassemia heterozygote with different forms of alpha-thalassemia in northeast Thailand. Blood Cells Mol Dis. 2011; 47(2):120-4. PMID: 21664157.

Apr 20, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Beta-thalassemia HBB/LCRB Pathogenic:1

Mar 27, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hb SS disease Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Beta-plus-thalassemia Pathogenic:1

Jun 10, 1982

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		1.3
PromoterAI		-0.14	Neutral
Mutation Taster		=34/66	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs33931746; hg19: chr11-5248329;