NM_000518.5:c.275T>G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000518.5(HBB):c.275T>G(p.Leu92Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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. L92P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 5.58

Publications

3 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 10 ACMG points.

PM1

In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 30 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 chr11-5226617-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 15338.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.275T>G	p.Leu92Arg	missense_variant	Exon 2 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.275T>G	p.Leu92Arg	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

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

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 30, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb Caribbean variant (HBB: c.275T>G; p.Leu92Arg, also known as Leu91Arg when numbered from the mature protein, rs33917785), is reported in the literature in the heterozygous state or in combination with Hb S in individuals with mild anemia or normal hematology (see link to HbVar and references therein, Ahern 1976). In vitro functional analyses demonstrate a mildly unstable protein with decreased oxygen affinity (Ahern 1976). This variant is also reported in ClinVar (Variation ID: 15131), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 92 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.885). However, given the limited amount of clinical and functional data, the significance of the Hb Caribbean variant is uncertain at this time. References: Link to HbVar for Hb Caribbean: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=428 Ahern E et al. Haemoglobin caribbean beta91 (F7) Leu replaced by Arg: a mildly haemoglobin with a low oxygen affinity. FEBS Lett. 1976 Oct 15;69(1):99-102. PMID: 992050. -

HEMOGLOBIN CARIBBEAN

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

0.54

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

4.0

H;H;.

PhyloP100

5.6

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.4

D;.;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.030

D;.;.

Polyphen

0.97

D;D;.

Vest4

0.96

MutPred

0.87

Loss of stability (P = 0.0071);Loss of stability (P = 0.0071);Loss of stability (P = 0.0071);

MVP

0.93

MPC

0.28

ClinPred

0.99

GERP RS

5.2

PromoterAI

0.014

Neutral

(source)

Varity_R

0.90

gMVP

0.96

Mutation Taster

=1/99

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over