rs121909825

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1PM2BP4_ModerateBP6_Very_Strong

The NM_000518.5(HBB):c.262A>C(p.Thr88Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,996 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T88I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -1.25

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 -6 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000518.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25903952).

BP6

Variant 11-5226630-T-G is Benign according to our data. Variant chr11-5226630-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 15489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.262A>C	p.Thr88Pro	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.262A>C	p.Thr88Pro	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251426

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000827

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000722

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 27, 2018	The HBB c.262A>C; Thr87Pro variant, also known as Hb Valletta, is reported in the literature, typically in linkage to the Hb F-Malta-I variant, in individuals affected with beta-thalassemia (Perrinello 2008, Scerri 1993) and in healthy individuals (Giambona 2006, Kutlar 1991, HbVar database and references therein). One individual with beta-thalassemia who carried the Thr87Pro variant was also homozygous for a pathogenic HBB variant (Parrinello 2008). Heat stability assays on Thr87Pro variant protein indicate this variant has normal stability (Kutlar 1991). The variant is listed ClinVar (Variation ID: 15489) and is found in the non-Finnish European population on six chromosomes in the Genome Aggregation Database. The threonine at residue 87 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on available information, the variant is considered likely benign. References: Link to HbVar database for Hb Valletta: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=417 Giambona A et al. Analysis of delta-globin gene alleles in the Sicilian population: identification of five new mutations. Haematologica. 2006 Dec;91(12):1681-4. Kutlar F et al. The linkage of Hb Valletta [alpha 2 beta 287(f3)Thr----Pro] and Hb F-Malta-I [alpha 2G gamma 2117(G19)His----Arg] in the Maltese population. Hum Genet. 1991 Apr;86(6):591-4. Perrinello G et al. Fever of unclear origin and cytopenia because of acute splenic sequestration in a young immunocompetent carrier of beta-globin mutation for Hb Valletta. Am J Med Sci. 2008 Dec;336(6):508-11. Scerri CA et al. The beta + IVS, I-NT no. 6 (T --> C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta. Br J Haematol. 1993 Apr;83(4):669-71. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2022	Variant summary: HBB c.262A>C (p.Thr88Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 252054 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant is found in 1.8% of the Maltese population (Kutlar_1991) and happens to be in tight linkage disequilibrium with the fetal Hb variant Hb F-Malta-I (HBG2 c.353A>G (p.His118Arg)). The variant has been reported in individuals in compound heterozygosity with a beta-thal causing variant (c.93+6T>C) whose hematological findings were similar to those detected in a simple heterozygous state (thalassemia trait), providing supportive evidence for a benign role (Scerri_1993). At least one publication, Kutlar_1991, reported heat stability experiments on mixtures of equal quantities of Hb A and Hb Valletta and on red cell lysates of two adult Hb Valletta heterozygotes, and showed normal stability. Another ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

beta Thalassemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 30, 2021

- -

HEMOGLOBIN VALLETTA

Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.13

Cadd

Benign

1.5

Dann

Benign

0.70

DEOGEN2

Benign

0.022

T;T;.;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.13

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.12

N;N;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.48

N;.;.;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.013

D;.;.;D

Sift4G

Benign

0.11

T;.;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.81

MVP

0.47

MPC

0.078

ClinPred

0.066

GERP RS

-11

Varity_R

0.26

gMVP

0.83

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

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