rs34196559

Positions:

• chr11-5227027-CTGTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000518.5(HBB):​c.-10_-7del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,423,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: HBB NM_000518.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:2
• Conservation: PhyloP100: 0.544

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-5227027-CTGTT-C is Benign according to our data. Variant chr11-5227027-CTGTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 495971.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.-10_-7del		5_prime_UTR_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.-10_-7del		5_prime_UTR_variant	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251080 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000197 AC: 28 AN: 1423342 Hom.: 0 AF XY: 0.0000113 AC XY: 8 AN XY: 710602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000186

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

beta Thalassemia Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 05, 2018	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 21, 2016

Variant summary: c.-10_-7delAACA affects non-conserved nucleotides, resulting in deletion of 4 nucleotides in the 5UTR region. Mutation taster predicts benign outcome. 4/5 in silico toosl via Alamut predict no significant change on the RNA splicing sites, ESEfinder predicts gain of binding motif for RNA splicing enhancer. However, these predictions should be taken with caution as Alamut tools are meant to analyze UTR regions, however, based on the topology of the region around this mutation does not include any regulatory elements (Sgourou, 2004). This variant was found in 6/121126 control chromosomes at a frequency of 0.0000495, predominantly observed in East Asian subpopulation with MAF of 0.000465 (4/8604 chr), which does not exceed the maximal expected frequency of a pathogenic allele (0.0111803). This variant has been reported both in cis and trans with known b-thal-0 variants in individuals presented with b-thal trait, suggesting that the variant in interest does not contribute to the thalassemic phenotype in these pts. Moreover, 2 individual, heterozygous for the variant of interest, had normal hematological parameters, suggesting that the variant is rare benign polymorphism. Functional studies so far yielded conflicting results ranging from no effect to a minor decrease steady state levels of mRNA to 70.6% compared with the wild type gene when different experimental systems were used (Frances, 1993; Sgourou, 2004). Taking togeter, the variant is likely to be a benign polymorphism, however, more clinical data as well as results of translational studies needed to evaluate the variant with confidence. Therefore, the variant was scored as likely benign until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs34196559; hg19: chr11-5248257;