chr11-5225683-C-T

Variant names:

• chr11-5225683-C-T
• rs33947020
• NM_000518.5:c.359G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000518.5(HBB):​c.359G>A​(p.Gly120Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,780 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G120A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.58
• Publications: 3 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 28 uncertain in NM_000518.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000518.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.359G>A	p.Gly120Asp	missense	Exon 3 of 3	NP_000509.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	ENST00000335295.4	TSL:1 MANE Select	c.359G>A	p.Gly120Asp	missense	Exon 3 of 3	ENSP00000333994.3
	HBB	ENST00000647020.1		c.359G>A	p.Gly120Asp	missense	Exon 3 of 3	ENSP00000494175.1
	HBB	ENST00000475226.1	TSL:2	n.291G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251278 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000479 AC: 7 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Jun 27, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 10, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple individuals with mild anemia or normal clinical and hematological parameters (Schneider et al., 1976; Basak et al., 2014; Kutlar et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24471829, 11829, 31553106, 24802353, 19429541, 33054450)

Mar 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.359G>A (p.Gly120Asp) variant (also known as Hb Fannin-Lubbock I) has been reported in the published literature as a slightly unstable hemoglobin variant with normal oxygen affinity (PMIDs: 19958195 (2009), 11829 (1976), 11828 (1976)). Heterozygosity for the Hb Fannin-Lubbock I variant is associated with a normal clinical presentation (PMIDs: 37782073 (2023), 24802353 (2014), 11829 (1976)). However, this variant was found in a homozygous infant that showed a mild Heinz body hemolytic anemia (PMID: 19958195 (2009)). When a second variant is found on the same chromosome, this complex allele is known as Hb Fannin-Lubbock II (PMIDs: 7852084 (1994), 17915134 (2007)). The frequency of this variant in the general population, 0.00017 (6/34586 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

Oct 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Fannin-Lubbock I variant (HBB: c.359G>A; p.Gly120Asp, also known as Gly119Asp when numbered from the mature protein; rs33947020; HbVarID: 699) has been reported as a homozygote in an individual with mild anemia and Heinz bodies and was considered slightly unstable (Ibarra 2009). However, this variant has also been described in the heterozygous state in multiple individuals with normal hematology, it does not segregate with abnormal hematological values in families, and it has not been associated with significant clinical symptoms when found with Hb S (Basak 2014, Moo-Penn 1976, Welsh 2015, HbVar database and references therein). Functional analyses indicate normal oxygen binding and reaction with 2,3-bisphosphoglycerate (Moo-Penn 1976). This variant is reported in ClinVar (Variation ID: 242712). It is found in the Latino population with an allele frequency of 0.017% (6/34586 alleles) in the Genome Aggregation Database. The glycine at codon 120 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.63). Based on the above information, the variant is considered to be likely benign. REFERENCES Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Basak J et al. Fannin-Lubbock-I (alpha2beta2¹¹?(GLY>ASP)), a rare mutation in the beta-globin gene, has been detected for the first time in a Hindu Brahmin family in West Bengal, India. Cell Mol Biol Lett. 2014 Jun;19(2):277-83. PMID: 24802353. Moo-Penn WF et al. Hemoglobin Fannin-Lubbock (alpha2 beta 2 119 (GH2) Gly replaced by Asp). A new hemoglobin variant at the alpha1 beta 1 contact. Biochim Biophys Acta. 1976 Dec 22;453(2):472-7. PMID: 11828. Ibarra B et al. HB Fannin-Lubbock-I with a single GGC>GAC mutation at beta119(GH2)Gly-->Asp in a homozygous Mexican patient. Hemoglobin. 2009;33(6):492-7. PMID: 19958195. Welsh KJ et al. An unusual case of heterozygous hemoglobin S/hemoglobin Fannin-Lubbock misidentified by capillary hemoglobin electrophoresis. Ann Clin Lab Sci. 2015 Spring;45(2):199-201. PMID: 25887875.

not specified Uncertain:1

Apr 02, 2024

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.359G>A (p.Gly120Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251278 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in multiple patients with mild anemia or no hemological abnormalities in heterozygous or homozygous state without clear evidence supporting the pathogenicity of this variant (Schneider_1976, Ibarra_2009, Basak_2014). Heterozygous complex allele c.334G>C-c.359G>A has been reported in five Spanish individuals with no hemological abnormalities (Qin_1994). Experimental evidence has shown this variant to be a slightly unstable hemoglobin variant, with normal oxygen affinity (eg. Schneider_1976). The following publications have been ascertained in the context of this evaluation (PMID: 6859036, 19429541, 7852084, 24802353, 19958195, 11829, 20184100). ClinVar contains an entry for this variant (Variation ID: 242712). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		1.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.055	T
Polyphen		0.74	P
Vest4		0.57
MutPred		0.69		Loss of ubiquitination at K121 (P = 0.0716)
MVP		0.97
MPC		0.084
ClinPred		0.43	T
GERP RS		3.8
Varity_R		0.88
gMVP		0.61
Mutation Taster		=9/91	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: rs33947020; hg19: chr11-5246913;