chr11-5227021-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000518.5(HBB):c.1A>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

HBB
NM_000518.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.81

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

dominant beta-thalassemia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
hemoglobin M disease
Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
beta thalassemia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
beta-thalassemia HBB/LCRB
Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
sickle cell disease and related diseases
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
erythrocytosis, familial, 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Heinz body anemia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
sickle cell disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
beta-thalassemia intermedia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
beta-thalassemia major
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
delta-beta-thalassemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin C disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin C-beta-thalassemia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin E disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin E-beta-thalassemia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-beta-thalassemia disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin c disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin d disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin E disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HBB links:

ENSG00000298932 (HGNC:):

ENSG00000298932 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 152 pathogenic variants. Next in-frame start position is after 56 codons. Genomic position: 5226726. Lost 0.374 part of the original CDS.

PS1

Another start lost variant in NM_000518.5 (HBB) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5227021-T-C is Pathogenic according to our data. Variant chr11-5227021-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 439140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152170

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74482

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2112

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:2

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

not provided

Pathogenic:2

Jun 22, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBB c.1A>G; p.Met1? variant (rs34563000), also known as Met1Val or initiation codon ATG->GTG, is reported in the literature in several heterozygous individuals affected with beta-thalassemia minor (Liu 2011, Perea 2004, HbVar database and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical translation initiation codon and is predicted to result in an aberrant or absent protein. Other variants that affect the HBB initiation codon have been reported in individuals with beta-thalassemia or microcytic anemia and are considered pathogenic (HbVar database and references therein). Based on available information, the c.1A>G variant is considered to be pathogenic. References: Link to c.1A>G in HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=775 Liu SC et al. Molecular lesion frequency of hemoglobin gene disorders in Taiwan. Hemoglobin. 2011;35(3):228-36. Perea FJ et al. Molecular spectrum of beta-thalassemia in the Mexican population. Blood Cells Mol Dis. 2004 Sep-Oct;33(2):150-2.

Hemoglobinopathy

Pathogenic:1

Feb 09, 2018

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.1A>G alters the initiation codon (i.e. ATG coding for methionine to a triplet GTG coding for valine, so the predicted protein level name would be p.Met1Val), and it is expected that the next available, downstream ATG codon will be used as a translational start site. However, as it is out of frame (located at codons 21-22), this would result in a frameshift followed by an early termination (at the next in-frame stop codon 118 nucleotides downstream), likely leading to a missing/non-functional protein product (Hattori 1991). Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245874 control chromosomes. The c.1A>G variant has been reported in the literature in multiple individuals in the heterozygous state causing Beta Thalassemia Minor (e.g. Hattori 1991, Huisman 1997, Ohba 1997, Perea 2004, Liu 2011), however it is expected that in homozygosity and/or compound heterozygosity with a severe variant, this variant is likely to cause the BTHAL MJR phenotype. Other changes affecting the initiation codon (such as: c.2T>G (p.Met1Arg), c.2T>C (p.Met1Thr), c.3G>A (p.Met1Ile)) have also been found in HBB patients (source: HGMD). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and classified the variant as 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

Mar 25, 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_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.032

T;T;.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.0

.;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

6.8

PROVEAN

Benign

-2.1

N;.;.;N

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;.;.;D

Sift4G

Uncertain

0.039

D;.;.;.

Vest4

0.98

ClinPred

0.88

GERP RS

5.2

PromoterAI

-0.15

Neutral

(source)

Varity_R

0.74

gMVP

0.72

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over