11-5226939-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000518.5(HBB):c.83C>T(p.Ala28Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A28T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 7.26

Publications

8 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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 33 uncertain in NM_000518.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226940-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4071470.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.83C>T	p.Ala28Val	missense_variant	Exon 1 of 3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.83C>T	p.Ala28Val	missense_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251344

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460980

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726882

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111192

Other (OTH)

AF:

0.00

AC:

AN:

60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 24, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in the heterozygous state in a family with erythrocytosis (Baklouti et al., 1987); Observed in cis with another HBB variant and with an -globin gene triplication in a family with thalassemia intermedia, anemia, and splenomegaly (Dipanwita Das et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as Hb Grange-Blanche [27(B9) Ala>Val]; This variant is associated with the following publications: (PMID: 3666141, Das2013[article], 25332589, 17949282, 3955238) -

HEMOGLOBIN GRANGE-BLANCHE

Other:1

Dec 12, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.052

T;T;.;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

.;D;T;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.6

M;M;.;.

PhyloP100

7.3

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;.;.;N

REVEL

Pathogenic

0.78

Sift

Uncertain

0.013

D;.;.;D

Sift4G

Uncertain

0.018

D;.;.;.

Polyphen

0.61

P;P;.;.

Vest4

0.50

MutPred

0.74

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.89

MPC

0.040

ClinPred

0.90

GERP RS

5.2

PromoterAI

-0.0066

Neutral

(source)

Varity_R

0.59

gMVP

0.83

Mutation Taster

=9/91

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over