Variant chr11-5227127-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: -1.48

Variant links:

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]

HBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.-106G>C		5_prime_UTR_variant	1/3			ENSP00000494175	P1
HBB	ENST00000380315.2 linkuse as main transcript	c.-18-88G>C		intron_variant		5		ENSP00000369671

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000286

AC XY:

101

AN XY:

353240

show subpopulations

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:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74476

show subpopulations

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.:

Bravo

AF:

0.000370

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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:1Uncertain: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

DANN

Benign

0.75

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over