11-5227159-G-T

Position:

• chr11-5227159-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000647020.1(HBB):​c.-138C>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 0.00000905 in 552,662 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1 O:1
• Conservation: PhyloP100: 1.75

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5227159-G-T is Pathogenic according to our data. Variant chr11-5227159-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393701.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Pathogenic=5, Uncertain_significance=1}. Variant chr11-5227159-G-T 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.-138C>A		5_prime_UTR_variant	1/3			P1
HBB	ENST00000380315.2	c.-18-120C>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000905 AC: 5 AN: 552662 Hom.: 0 Cov.: 5 AF XY: 0.00000669 AC XY: 2 AN XY: 298996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000518

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000486

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000330

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 27, 2018	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The c.-138C>A variant in HBB (also known as -88C>A) has been reported in the homozygous and compound heterozygous state in numerous individuals with Beta Thalassemia (selected publications: Rund 1991 PMID: 1986379, Atroshi 2021 PMID: 34794358, Hassan 2014 PMID: 24880717, Turner 2016 PMID: 27756326, Ozkinay 2015 PMID: 26076395, El-Shanshory 2014 PMID: 25408857, Baysal 2011 PMID: 22074124, Sirdah 2013 PMID: 23321370, Vetter 1997 PMID: 9163586). It has been reported in ClinVar (Variation ID 393701) but was absent from large population databases. This variant lies in a known transcription binding site (CACCC box) where other clinically significant HBB variants (such as c.-140C>T, c.-138C>T, c.-137C>G and c.-137C>T) have been identified. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PS4, PM1. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 07, 2021	The HBB c.-138C>A variant (also known as -88C>A) not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant reduces the binding of transcription factors and causes decreased transcription of the beta-globin gene. In the published literature, the variant has been reported in individuals with beta(+)-thalassemia (PMIDs: 26948378 (2017), 26076395 (2015), 23321370 (2013), 20437613 (2010), 1986379 (1991)). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	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 β-thalassemia intermedia (PMID: 9163586, 21232998, 22180324, 25408857, 26076396). It has also been observed to segregate with disease in related individuals. This variant is also known as -88C>A in literature. ClinVar contains an entry for this variant (Variation ID: 393701). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 23, 2020	- -

Hemoglobinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 01, 2018

Variant summary: HBB c.-138C>A is located in the untranscribed region upstream of the HBB gene region. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant lies in a known transcription binding site (CACCC box) where other HBB variants (such as c.-140C>T, c.-138C>T, c.-137C>G and c.-137C>T) are known to be pathogenic for BTHAL ITMD. The variant was absent in 30972 control chromosomes (gnomAD). The variant, c.-138C>A, has been reported in the literature in multiple individuals affected with Beta Thalassemia (Rund_1991, El-Shanshory_2014, Baysal_2011, Sirdah_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1991

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs33944208; hg19: chr11-5248389;