11-5227158-G-T

Variant names:

• chr11-5227158-G-T
• rs33941377
• ENST00000647020.1:c.-137C>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.-137C>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 0.0000329 in 152,136 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: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 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-T is Pathogenic according to our data. Variant chr11-5227158-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227158-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000647020.1	c.-137C>A		5_prime_UTR_variant	Exon 1 of 3			ENSP00000494175.1
HBB	ENST00000380315.2	c.-18-119C>A		intron_variant	Intron 2 of 3	5		ENSP00000369671.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 554166 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 299838

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 AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Nov 27, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-137C>A variant (rs33941377; HbVar ID 757), also known as -87C>A, is reported in the literature as a mild beta(+) thalassemia variant and is reported in several individuals with beta thalassemia intermedia (Coleman 1992, Danjou 2015, Huisman 1992). This variant is located in the HBB promoter in the CACCC box that promotes gene transcription, and functional assays indicate that this variant results in reduced transcriptional activity (Kircher 2019). This variant is reported in ClinVar (Variation ID: 36285), but is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Coleman MB et al. The -87 (C----A) beta(+)-thalassemia mutation in a black family. Hemoglobin. 1992 16:399-401. PMID: 1428943. Danjou F et al. A genetic score for the prediction of beta-thalassemia severity. Haematologica. 2015 100:452-457. PMID: 25480500. Huisman TH. The beta- and delta-thalassemia repository. Hemoglobin. 1992 16:237-258. PMID: 1517101. Kircher M et al. Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. Nat Commun. 2019 10:3583. PMID: 31395865. -

Jan 02, 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 present in population databases (rs33941377, gnomAD 0.03%). This variant has been observed in individual(s) with beta-thalassemia (PMID: 1428943, 12779270, 24828949). 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 c.-87C>A. ClinVar contains an entry for this variant (Variation ID: 36285). Studies have shown that this variant alters HBB gene expression (PMID: 3457470). This variant disrupts the c.-137C nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2837728, 6188062). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

beta Thalassemia Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 09, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beta thalassemia intermedia Pathogenic:1

Nov 24, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.-137C>A is a conserved nucleotide located in the untranscribed region upstream of the HBB gene region in the CACCC functional element. The variant allele was found at a frequency of 9.6e-05 in 31398 control chromosomes (gnomAD). c.-137C>A has been reported in the literature in individuals affected with Beta Thalassemia Intermedia (e.g. Coleman_1992, Arpaci_2021) and in Beta-Thalassemia Major patients (e.g. Sirichotiyakul_2003). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating transcription levels, and showed the variant results in about 40% of normal activity (Myers_1986). In addition, other substitutions at the same nucleotide are known to be disease causing for BTHAL-intermedia (c.-137C>T and c.-137C>G). The C>T substitution results in a moderate reduction in transcription activity (Kulozik_1991), while the C>G substitution at the same nucleotide position showed significantly lower levels of RNA transcripts via RNA blotting and S1 Nuclease Mapping (Treisman_1983). Five ClinVar submitters (evaluation after 2014) cite the variant as Pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.65

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;