11-5225654-C-G

Variant names:

• chr11-5225654-C-G
• rs35939430
• NM_000518.5:c.388G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000518.5(HBB):​c.388G>C​(p.Ala130Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. A130V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 0.923
• Publications: 8 publications found

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

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 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 chr11-5225653-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15245.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 11-5225654-C-G is Pathogenic according to our data. Variant chr11-5225654-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15146.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.388G>C	p.Ala130Pro	missense_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.388G>C	p.Ala130Pro	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251326 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.A130P in HBB (NM_000518.5) has been previously reported as Hb Crete (Christopoulou G et al, 2004). The p.A130P variant is observed in 1/1,13,636 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools are contradictory in their predictions and the variant is weakly conserved across species. For these reasons, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Jul 03, 2025

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: HBB c.388G>C (p.Ala130Pro), also referred to as Hb Crete, results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 251326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.388G>C has been reported in a homozygous individual with a complex phenotype of erythrocytosis and functional anemia (Papassotitiou_2005). It has also been observed in several heterozygous and compound heterozygous individuals with abnormal red blood cell morphology and mild erythocytosis, but who were mostly clinically asymptommatic with no splenomegaly, and no history of thrombosis (e.g. Maniatis_1979, Christopoulou_2004, Arslan_2011, Komninaka_2024). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. Functional studies have shown that the variant results in reduced stability, moderately decreased cooperativity, a normal Bohr effect and increased oxygen affinity (e.g. Maniatis_1979, Christopoulou_2004, Papassotitiou_2005); however, these findings do not allow for convincing conclusions to be made about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 15658190, 36184, 27264598, 15885607, 38256595). ClinVar contains an entry for this variant (Variation ID: 15146). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Mar 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.388G>C (p.Ala130Pro) variant has been reported in the published literature in a homozygous individual with a complex phenotype including mild erythrocytosis and functional anemia as well as in heterozygous carriers who are either described as having normal hemoglobin levels, however, with hematological data usually associated with thalassemia trait (PMID 15885607 (2005)) or affected with mild hemolytic anemia (PMID 15658190 (2004)). In addition, functional studies have described this variant as having increased oxygen affinity, decreased cooperativity, and being unstable (HbVar http://globin.bx.psu.edu/, Ithanet http://www.ithanet.eu/, PMID 36184 (1979) and 15885607 (2005)). The frequency of this variant in the general population, 0.000004 (1/251326 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

HEMOGLOBIN CRETE 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	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	4.2	H;H
PhyloP100		0.92
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.014	D;.
Polyphen		1.0	D;D
Vest4		0.85
MVP		0.91
MPC		0.15
ClinPred		0.98	D
GERP RS		0.61
Varity_R		0.75
gMVP		0.99
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs35939430; hg19: chr11-5246884;