rs111645889

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP5

The NM_000518.5(HBB):c.389C>T(p.Ala130Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A130P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:1

Conservation

PhyloP100: 3.56

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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5225654-C-G is described in Lovd as [Pathogenic].

PP5

Variant 11-5225653-G-A is Pathogenic according to our data. Variant chr11-5225653-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15245.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}. Variant chr11-5225653-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.389C>T	p.Ala130Val	missense_variant	3/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBB	ENST00000335295.4 linkuse as main transcript	c.389C>T	p.Ala130Val	missense_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1 linkuse as main transcript	c.389C>T	p.Ala130Val	missense_variant	3/3			ENSP00000494175	P1
HBB	ENST00000633227.1 linkuse as main transcript	c.*205C>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000488004
HBB	ENST00000475226.1 linkuse as main transcript			downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251302

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.000308

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 28, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. ClinVar contains an entry for this variant (Variation ID: 15245). This variant is also known as Hb La Desirade. This missense change has been observed in individual(s) with sickle cell anemia (PMID: 33489049). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive beta thalassemia (PMID: 3557994, 27670359); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs111645889, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 130 of the HBB protein (p.Ala130Val). -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 27, 2023	The frequency of this variant in the general population, 0.00024 (6/24966 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Individuals who are heterozygous for this variant have been described as having a normal clinical presentation (PMID: 33489049 (2021)). This variant has also been observed in the compound heterozygous state in patients who had moderate to severe anemia or beta(0)-thalassemia (PMIDs: 32411010 (2020), 27670359 (2017), and 3557994 (1986)). Functional studies indicate that this variant is unstable with decreased oxygen affinity (PMID: 3557994 (1986) and 31553106 (2020)). Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 29, 2024	The Hb La Desirade variant (HBB: c.389C>T; p.Ala130Val, also known as Ala129Val when numbered from the mature protein; rs111645889, HbVar ID: 531, ClinVar Variation ID: 15245) has been reported in-trans to pathogenic HBB variants (Hb C, beta0-thalassemia, Hb E) in asymptomatic individuals (Merault 1986, Kamseng 2017). However, when found in-trans with Hb S, variable presentations have been described including asymptomatic individuals and individuals with mild symptoms of sickle cell disease (e.g. recurrent mild painful episodes including chest and back pain, bilateral renal stones, splenomegaly, and hepatomegaly; Alkindi 2021). Functional study of purified Hb La Desirade indicates instability and a slight decrease in oxygen affinity (Merault 1986). This variant does not separate from hemoglobin A using standard electrophoresis (Alkindi 2021, HbVar ID: 531). This variant is observed on six chromosomes in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.818). Based on available information, the Hb La Desirade is likely pathogenic for mild sickle cell disease when found in-trans to Hb S. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Alkindi S et al. Clinical and Laboratory Features of Hemoglobin La Desirade Variant in Association with Sickle Cell and Alpha Thalassemia Genes. Mediterr J Hematol Infect Dis. 2021 Jan 1;13(1):e2021010. PMID: 33489049. Kamseng P et al. Low oxygen saturation and severe anemia in compound heterozygous Hb Louisville (beta42(CD1)Phe>Leu) and Hb La Desirade (beta129(H7)Ala>Val). Hematology. 2017;22(2):114-118. PMID: 27670359. Merault G et al. Hemoglobin La Desirade alpha A2 beta 2 129 (H7) Ala----Val: a new unstable hemoglobin. Hemoglobin. 1986;10(6):593-605. PMID: 3557994. -

Hemoglobinopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 05, 2024

Variant summary: HBB c.389C>T (p.Ala130Val; also known as Hb La Desirade) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251302 control chromosomes (gnomAD). The variant, c.389C>T, has been reported in the literature in multiple asymptomatic carriers (Alkindi_2021). To our knowledge, no homozygous occurrence was reported, however, the variant was reported together with a beta-0-thal variant in a clinically asymptomatic individual, who had elevated reticulocyte count (Merault_1986). The variant was also reported in compound heterozygosity with HbC (c.19G>A (p.Glu7Lys)), and HbE (c.79G>A (p.Glu27Lys)), in clinically asymptomatic individuals (Merault_1986, Kamseng_2017). In addition, this variant was reported in compound heterozygosity with HbS (c.20A>T (p.Glu7Val)) in several individuals who were affected with mild sickle cell anemia (Merault_1986, Alkindi_2021). These data indicate that the variant maybe associated with a milder disease phenotype, which is dependent on the variant in trans. At least one publication reported experimental evidence indicating that the variant results in a mild decrease in oxygen affinity and precipitation during the isopropanol test, suggestive of an unstable hemoglobin (Merault 1986). The following publications have been ascertained in the context of this evaluation (PMID: 20437613, 33489049, 32411010, 25677748, 26635043, 27670359, 15727901, 17932132, 3557994, 22995479, 26594346, 31553106, 37845805, 35143361). ClinVar contains an entry for this variant (Variation ID: 15245). In summary, though the variant has not been reported in homozygous form in affected individuals, however, it was reported in several individuals in compound heterozygosity with HbS, who were affected with a milder sickle cell anemia phenotype. Therefore, based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hb SS disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

HEMOGLOBIN LA DESIRADE

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

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

0.084

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

.;T

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.5

D;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0080

D;.

Sift4G

Uncertain

0.039

D;.

Polyphen

0.42

B;B

Vest4

0.51

MVP

0.88

MPC

0.034

ClinPred

0.40

GERP RS

2.8

Varity_R

0.35

gMVP

0.94

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