11-5227101-A-T

Position:

• chr11-5227101-A-T

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.-80T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 851,138 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:7 O:1
• Conservation: PhyloP100: 2.19

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 11-5227101-A-T is Pathogenic according to our data. Variant chr11-5227101-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 15467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227101-A-T is described in Lovd as [Pathogenic]. Variant chr11-5227101-A-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.-80T>A		upstream_gene_variant		ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.-80T>A		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000352 AC: 3 AN: 851138 Hom.: 0 Cov.: 12 AF XY: 0.00000224 AC XY: 1 AN XY: 446818

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000536

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	HBB: PM3:Strong, PM1, PM2, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 15467). This variant has been observed in individual(s) with beta thalassemia (PMID: 1487424, 1917531, 3382401, 20854126). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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.-80T>A pathogenic variant (also known as -30T>A) is located in the TATA-box of the HBB gene promoter, and decreases transcription of the beta-globin gene. This variant is associated with beta(+)-thalassemia. Individuals homozygous for this variant present with beta-thalassemia intermedia or major (PMIDs: 20854126 (2010), 1487424 (1992), 1917531 (1991), 3382401 (1988)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

beta Thalassemia Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 05, 2018

The HBB c.-80T>A variant, also known as -30 (T>A), is published in the medical literature in individuals with beta thalassemia intermedia when in the homozygous state and in individuals with a deletion on the opposite chromosome (see link to HbVar database, Fei 1988, Griffon 2010). The variant is listed in the ClinVar database (Variation ID: 15467) and the dbSNP variant database (rs33980857). This variant occurs in the conserved promoter region (Giardine 2011) and is predicted to affect transcription factor binding , thus reducing but not completely abrogating the amount of message produced from that chromosome (beta +). Considering available information, this variant is classified as pathogenic. References: Link to variant in HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=765&.cgifields=histD Fei YJ et al. Beta-thalassemia due to a T----A mutation within the ATA box. Biochem Biophys Res Commun. 1988 Jun 16;153(2):741-7. Giardine B et al. Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach. Nat Genet. 2011 Mar 20;43(4):295-301. Griffon C et al. Severe B-thalassemia intermedia in a compound heterozygous patient for the -30 (T>A) B(+)-thalassemia mutation and the D(0)B(+)-Senegalese deletion. Hemoglobin. 2010;34(5):505-8. -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs33980857; hg19: chr11-5248331;