11-5227017-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000518.5(HBB):c.5T>C(p.Val2Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000025 in 1,596,872 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 4.96

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.5T>C	p.Val2Ala	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.5T>C	p.Val2Ala	missense_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251128

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135724

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1444680

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000182

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The HBB c.5T>C (p.Val2Ala) variant, also known as Hb Raleigh, causes a missense change involving the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that Hb Raleigh had a lower oxygen affinity than Hb A throughout the pH range examined but did not affect protein stability (Moo-Penn_1977, Landin_1993). Also, 2,3-diphosphoglycerate and inositol hexaphosphate cofactors addition had less effect on the oxygen affinity of Hb Raleigh than on that of Hb A with chloride ions having the opposite effect. This variant was found in 1/245880 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant is widely regarded as clinically silent variant. It was reported in several individuals with no clinical data (Chen_1998, Thongnoppakhun_2009, Canatan_2016,) or normal hematological values in heterozygosity (Landin_2009), including one report where it was occurring in 5 members of the same family where the proband (compound heterozygous with Hb Russ) had normal hematological values (Moo Penn_1977). In addition, an individual who had this variant in compound heterozygous state with HbS showed no specific features of hemoglobinopathy or beta-thalassemia (Sofronescu_2011). Furthermore, an individual, who was a double heterozygote for this variant and alfa gene deletion (c.a-3.7), was generally healthy but had a mild anemia due to the alfa gene deletion (Jain_2011). This structural variant produces spurious HbA1c measurement depending upon methods used, impeding the use of Hb glycosylation as a means to monitor glucose control in diabetic patients with Hb-Raleigh (Chen_1998, Vandewiele_2010, Sofronescu_2011, Singha_2011, Jain_2011). Taken together, this variant is classified as a VUS-possibly benign. -

beta Thalassemia

Uncertain:1

Oct 24, 2018

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

May 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Raleigh variant (HBB: c.5T>C; p.Val2Ala, also known as Val1Ala when numbered from the mature protein; HbVar ID: 217; rs33949930) has been described in the heterozygous state in asymptomatic individuals with normal hematological parameters (HbVar and references therein). This variant is reported in ClinVar (Variation ID: 15323), and is found on only one chromosome (1/251128 alleles) in the Genome Aggregation Database. The valine at codon 2 is highly conserved and functional studies of this variant protein demonstrate reduced oxygen affinity and dissociation (HbVar and references therein). Additionally, this variant has been reported to interfere with measurements of HbA1c (Sofronescu 2011). Based on available information, this variant is considered to be likely benign. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Sofronescu AG et al. Unexpected hemoglobin A1c results. Clin Chem. 2011 Feb;57(2):153-6. PMID: 21278358. -

HEMOGLOBIN RALEIGH

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

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.11

T;T;.;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

.;T;T;T

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

3.4

M;M;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.5

D;.;.;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0030

D;.;.;D

Sift4G

Uncertain

0.0040

D;.;.;.

Polyphen

0.88

P;P;.;.

Vest4

0.87

MutPred

0.70

Loss of stability (P = 0.0128);Loss of stability (P = 0.0128);Loss of stability (P = 0.0128);Loss of stability (P = 0.0128);

MVP

0.80

MPC

0.043

ClinPred

0.78

GERP RS

4.0

Varity_R

0.34

gMVP

0.83

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

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