rs34883338

chr11-5227163-G-A

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.-142C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 2.35

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 11-5227163-G-A is Pathogenic according to our data. Variant chr11-5227163-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227163-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000647020.1	c.-142C>T		5_prime_UTR_variant	1/3			P1
HBB	ENST00000380315.2	c.-18-124C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 544686 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 294650

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 18, 2023

The HBB c.-142C>T (also known -92C>T) variant is located in the promoter region of the HBB gene. It is described as mild promoter variant. Heterozygotes for this variant can be clinically asymptomatic, while compound heterozygous individuals for this variant and a Beta zero or severe Beta+ variant can develop thalassemia intermedia (PMID:7794779 (1995), 26041423 (2015), 26635043 (2016)). -

Beta thalassemia intermedia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 23, 2023

Variant summary: HBB c.-142C>T is located in the untranscribed region upstream of the HBB gene region. The variant was absent in 31398 control chromosomes (gnomAD). c.-142C>T has been reported in the literature in bi-allelic individuals affected with Beta Thalassemia Intermedia (examples: Rosatelli_1995, Aliveya_2018, Kimberland_1995). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant showed decreased protein expression and loss of interactions with transcription factors (Fauxman Bass, 2015). Kircher et al (Kircher_2018) also report reduced promoter activity for this variant. They speculate that this could be due to a known binding site for the erythroid Krppel factor (EKLF), a zinc-finger transcription factor in positions c.-142 to c.-136 that plays a critical role in erythropoiesis and regulation of beta-globin switching. The following publications have been ascertained in the context of this evaluation (PMID: 29893155, 26041423, 11857746, 8438884, 25910213, 18603555, 11857738, 12324499, 7599641, 31395865, 19103851, 7794779, 20704537). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1992

- -

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	-0.42
Cadd	Benign	16
Dann	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34883338; hg19: chr11-5248393;