11-5227013-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000518.5(HBB):c.9T>C(p.His3His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 1,605,108 control chromosomes in the GnomAD database, including 539,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 51260 hom., cov: 33)

Exomes 𝑓: 0.82 ( 488579 hom. )

Consequence

HBB
NM_000518.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -0.886

Publications

62 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 11-5227013-A-G is Benign according to our data. Variant chr11-5227013-A-G is described in ClinVar as Benign. ClinVar VariationId is 193106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000518.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.9T>C	p.His3His	synonymous	Exon 1 of 3	NP_000509.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HBB	ENST00000335295.4	TSL:1 MANE Select	c.9T>C	p.His3His	synonymous	Exon 1 of 3	ENSP00000333994.3
HBB	ENST00000485743.1	TSL:1	c.9T>C	p.His3His	synonymous	Exon 1 of 2	ENSP00000496200.1
HBB	ENST00000647020.1		c.9T>C	p.His3His	synonymous	Exon 1 of 3	ENSP00000494175.1

Frequencies

GnomAD3 genomes

AF:

0.816

AC:

124106

AN:

152044

Hom.:

51226

Cov.:

show subpopulations

Gnomad AFR

AF:

0.868

Gnomad AMI

AF:

0.971

Gnomad AMR

AF:

0.728

Gnomad ASJ

AF:

0.865

Gnomad EAS

AF:

0.490

Gnomad SAS

AF:

0.635

Gnomad FIN

AF:

0.786

Gnomad MID

AF:

0.870

Gnomad NFE

AF:

0.841

Gnomad OTH

AF:

0.825

GnomAD2 exomes

AF:

0.763

AC:

191549

AN:

251090

AF XY:

0.763

show subpopulations

Gnomad AFR exome

AF:

0.868

Gnomad AMR exome

AF:

0.659

Gnomad ASJ exome

AF:

0.868

Gnomad EAS exome

AF:

0.499

Gnomad FIN exome

AF:

0.790

Gnomad NFE exome

AF:

0.840

Gnomad OTH exome

AF:

0.796

GnomAD4 exome

AF:

0.816

AC:

1185386

AN:

1452948

Hom.:

488579

Cov.:

AF XY:

0.811

AC XY:

586986

AN XY:

723402

show subpopulations

African (AFR)

AF:

0.874

AC:

29090

AN:

33268

American (AMR)

AF:

0.668

AC:

29852

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.863

AC:

22510

AN:

26088

East Asian (EAS)

AF:

0.499

AC:

19777

AN:

39650

South Asian (SAS)

AF:

0.648

AC:

55746

AN:

86052

European-Finnish (FIN)

AF:

0.791

AC:

42258

AN:

53406

Middle Eastern (MID)

AF:

0.872

AC:

5016

AN:

5750

European-Non Finnish (NFE)

AF:

0.845

AC:

932633

AN:

1104014

Other (OTH)

AF:

0.808

AC:

48504

AN:

60022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

10789

21578

32368

43157

53946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20814

41628

62442

83256

104070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.816

AC:

124197

AN:

152160

Hom.:

51260

Cov.:

AF XY:

0.808

AC XY:

60082

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.868

AC:

36048

AN:

41516

American (AMR)

AF:

0.728

AC:

11126

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.865

AC:

3002

AN:

3470

East Asian (EAS)

AF:

0.490

AC:

2522

AN:

5148

South Asian (SAS)

AF:

0.636

AC:

3061

AN:

4814

European-Finnish (FIN)

AF:

0.786

AC:

8335

AN:

10602

Middle Eastern (MID)

AF:

0.864

AC:

254

AN:

294

European-Non Finnish (NFE)

AF:

0.841

AC:

57227

AN:

68010

Other (OTH)

AF:

0.821

AC:

1736

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1145

2290

3435

4580

5725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

868

1736

2604

3472

4340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.843

Hom.:

25631

Bravo

AF:

0.820

Asia WGS

AF:

0.573

AC:

1995

AN:

3476

EpiCase

AF:

0.842

EpiControl

AF:

0.845

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

beta Thalassemia (6)

not provided (4)

not specified (4)

alpha Thalassemia;C0002895: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 (1)

Fetal hemoglobin quantitative trait locus 1 (1)

Hb SS disease (1)

Hemoglobin E (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.47

(source)

DANN

Benign

0.41

PhyloP100

-0.89

PromoterAI

-0.025

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over