rs63750681

Positions:

• chr11-5227127-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000647020.1(HBB):​c.-106G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 812,098 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:7
• Conservation: PhyloP100: -1.48

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000647020.1	c.-106G>C		5_prime_UTR_variant	1/3			ENSP00000494175	P1
HBB	ENST00000380315.2	c.-18-88G>C		intron_variant		5		ENSP00000369671

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000300 AC: 198 AN: 659788 Hom.: 0 Cov.: 8 AF XY: 0.000286 AC XY: 101 AN XY: 353240

Gnomad4 AFR exome AF: 0.000167

Gnomad4 AMR exome AF: 0.000297

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.000970

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000370

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2024	Observed in apparent homozygous state in a patient with moderate microcytic anemia in the literature (PMID: 25754248); Also known as -56C>G; This variant is associated with the following publications: (PMID: 35615994, 29157184, 18081706, 25754248) -

beta Thalassemia Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 23, 2021	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 25, 2024

Variant summary: HBB c.-106G>C (also referred to as -56G>C) alters a non-conserved nucleotide located in the untranscribed promoter region upstream of the HBB gene, and therefore might affect gene expression. The variant allele was found at a frequency of 0.00035 in 31394 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia Intermedia (0.00035 vs 0.011), allowing no conclusion about variant significance. The variant, c.-106G>C, has been reported in the literature in a compound heterozygous patient together with a beta thalassemia major disease variant (c.92+1G>A), who had a beta thalassemia intermedia phenotype (Agouti_2008). The variant was also found in a homozygous individual, who displayed some features resembling to beta thalassemia minor, i.e. mild microcytic anemia, with low mean corpuscular hemoglobin concentration (Douzi_2015). These reports suggest that the variant might cause a milder phenotype, possibly affecting the beta gene expression. However, the variant was also reported in eight heterozygous individuals showing normal hematological values (i.e. being impossible to distinguish it from healthy, non-carrier subjects), and in at least three compound heterozygote patients carrying other globin disease variants, who showed phenotypes equivalent to patients carrying only the other alleles (Vinciguerra_2018, Belmokhtar_2022); therefore, these data suggest a benign role for the variant. 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: 18081706, 25754248, 21423179, 27718361, 26076395, 29157184, 35615994). ClinVar contains an entry for this variant (Variation ID: 36281). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Beta-thalassemia HBB/LCRB Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Hb SS disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs63750681; hg19: chr11-5248357;