11-5227161-G-C

Position:

• chr11-5227161-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000647020.1(HBB):​c.-140C>G variant causes a 5 prime UTR change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 3.60

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.5227161G>C		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000647020.1	c.-140C>G		5_prime_UTR_variant	1/3			ENSP00000494175.1
HBB	ENST00000380315.2	c.-18-122C>G		intron_variant		5		ENSP00000369671.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 5

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 19, 2021	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 12, 2023

The HBB c.-140C>G variant (also known -90C>G) variant is located in the promoter region of the HBB gene and has been reported in the published literature in an individual with beta(+) thalassemia (PMID: 28603845 (2017)). This variant reduces the binding of transcription factors and causes decreased transcription of the beta-globin gene (ITHANET (http://www.ithanet.eu/)). 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. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 24, 2024

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 21, 2024

Variant summary: HBB c.-140C>G variant leads to a substitution in the 5' UTR conserved promoter sequence (CACCC box) at a conserved nucleotide. The transcription factor erythroid Kruppel-like factor (EKLF) specifically activates the b-globin gene by interacting with the proximal b-globin CACCC box, a known hot spot for thalassaemia mutations. It has been shown that EKLF requires both the proximal and distal CACCC boxes to maximally stimulate the b-globin gene, and thus changes to the CACCC boxes are expected to reduce HBB expression (PMID:15384985). Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 31402 control chromosomes (gnomAD). c.-140C>G has been reported in the literature in at least 4 heterozygous carrier members of a family, with the proband being reported with anemia, microcytosis, hypochromia and elevated HbA2 (e.g. Rizo-de la Torre_2017). The variant is reported in the Ithanet database as "globin gene causative mutation". Another substitution at the same position, c.-140C>T has been classified as a pathogenic variant by our laboratory and it is reported to impair mRNA synthesis (PMIDs: 3457470 and 14555318). Furthermore, other substitutions in the same CACCC box have been classified as pathogenic by our laboratory (e.g. c.-138C>T, c.-138C>A, c.-137C>G, c.-137C>T, c.-136C>G). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28603845, 33734896). ClinVar contains an entry for this variant (Variation ID: 495975). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34999973; hg19: chr11-5248391;