11-5225683-C-T

Position:

• chr11-5225683-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 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 Likely benign.

• 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

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 (HGNC:):

ACMG classification

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, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.359G>A	p.Gly120Asp	missense_variant	3/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.359G>A	p.Gly120Asp	missense_variant	3/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251278 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135792

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	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) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 27, 2024	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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 02, 2024

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 v4.3

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;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;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.8	H;H
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;P
Vest4		0.57
MutPred		0.69		Loss of ubiquitination at K121 (P = 0.0716);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

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

Other links and lift over

dbSNP: rs33947020; hg19: chr11-5246913;