11-5226561-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000485743.1(HBB):c.331G>C(p.Ala111Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 1,609,510 control chromosomes in the GnomAD database, including 542,678 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A111T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.82 ( 51514 hom., cov: 31)

Exomes 𝑓: 0.82 ( 491164 hom. )

Consequence

HBB
ENST00000485743.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -3.19

Publications

42 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
erythrocytosis, familial, 6
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
hemoglobin M disease
Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet
unstable hemoglobin disease
Inheritance: AD Classification: DEFINITIVE Submitted by: 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), Ambry Genetics, ClinGen
sickle cell disease and related diseases
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Heinz body anemia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
sickle cell disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
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 -18 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 13 uncertain in ENST00000485743.1

BP4

Computational evidence support a benign effect (MetaRNN=9.3192546E-7).

BP6

Variant 11-5226561-C-G is Benign according to our data. Variant chr11-5226561-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000485743.1. 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.315+16G>C		intron	N/A	NP_000509.1	D9YZU5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HBB	ENST00000485743.1	TSL:1	c.331G>C	p.Ala111Pro	missense	Exon 2 of 2	ENSP00000496200.1	A0A2R8Y7R2
HBB	ENST00000335295.4	TSL:1 MANE Select	c.315+16G>C		intron	N/A	ENSP00000333994.3	P68871
HBB	ENST00000647020.1		c.315+16G>C		intron	N/A	ENSP00000494175.1	P68871

Frequencies

GnomAD3 genomes

AF:

0.818

AC:

124382

AN:

151986

Hom.:

51464

Cov.:

show subpopulations

Gnomad AFR

AF:

0.874

Gnomad AMI

AF:

0.971

Gnomad AMR

AF:

0.728

Gnomad ASJ

AF:

0.865

Gnomad EAS

AF:

0.495

Gnomad SAS

AF:

0.645

Gnomad FIN

AF:

0.787

Gnomad MID

AF:

0.870

Gnomad NFE

AF:

0.841

Gnomad OTH

AF:

0.824

GnomAD2 exomes

AF:

0.765

AC:

192152

AN:

251156

AF XY:

0.765

show subpopulations

Gnomad AFR exome

AF:

0.874

Gnomad AMR exome

AF:

0.659

Gnomad ASJ exome

AF:

0.867

Gnomad EAS exome

AF:

0.502

Gnomad FIN exome

AF:

0.790

Gnomad NFE exome

AF:

0.840

Gnomad OTH exome

AF:

0.797

GnomAD4 exome

AF:

0.817

AC:

1190789

AN:

1457406

Hom.:

491164

Cov.:

AF XY:

0.813

AC XY:

589689

AN XY:

725362

show subpopulations

African (AFR)

AF:

0.881

AC:

29415

AN:

33396

American (AMR)

AF:

0.668

AC:

29844

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.863

AC:

22527

AN:

26108

East Asian (EAS)

AF:

0.505

AC:

20039

AN:

39680

South Asian (SAS)

AF:

0.660

AC:

56869

AN:

86150

European-Finnish (FIN)

AF:

0.791

AC:

42269

AN:

53418

Middle Eastern (MID)

AF:

0.873

AC:

5034

AN:

5766

European-Non Finnish (NFE)

AF:

0.845

AC:

935994

AN:

1107950

Other (OTH)

AF:

0.810

AC:

48798

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

10556

21112

31668

42224

52780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20920

41840

62760

83680

104600

<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:

0.818

AC:

124491

AN:

152104

Hom.:

51514

Cov.:

AF XY:

0.810

AC XY:

60198

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.874

AC:

36300

AN:

41520

American (AMR)

AF:

0.728

AC:

11124

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.865

AC:

3001

AN:

3468

East Asian (EAS)

AF:

0.495

AC:

2545

AN:

5144

South Asian (SAS)

AF:

0.646

AC:

3110

AN:

4812

European-Finnish (FIN)

AF:

0.787

AC:

8323

AN:

10576

Middle Eastern (MID)

AF:

0.864

AC:

254

AN:

294

European-Non Finnish (NFE)

AF:

0.841

AC:

57218

AN:

67998

Other (OTH)

AF:

0.821

AC:

1730

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1115

2230

3344

4459

5574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.833

Hom.:

9322

Bravo

AF:

0.822

TwinsUK

AF:

0.843

AC:

3127

ALSPAC

AF:

0.839

AC:

3235

ESP6500AA

AF:

0.870

AC:

3831

ESP6500EA

AF:

0.841

AC:

7229

ExAC

AF:

0.769

AC:

93406

Asia WGS

AF:

0.588

AC:

2049

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

beta Thalassemia (6)

not provided (4)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.038

(source)

DANN

Benign

0.37

FATHMM_MKL

Benign

0.0077

LIST_S2

Benign

0.20

MetaRNN

Benign

9.3e-7

PhyloP100

-3.2

GERP RS

-6.3

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over