chr11-5226642-C-A

Variant names:

• chr11-5226642-C-A
• rs33930385
• NM_000518.5:c.250G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000518.5(HBB):​c.250G>T​(p.Gly84Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G84D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.0570

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]

ACMG classification

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 chr11-5226642-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.250G>T	p.Gly84Cys	missense_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.250G>T	p.Gly84Cys	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251436 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jul 18, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Ta-Li variant (HBB: c.250G>T; p.Gly84Cys, also known as Gly83Cys when numbered from the mature protein, rs33930385, HbVar ID: 410) is reported in the literature in several related individuals with no apparent anemia (Blackwell 1971, HbVar database). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.612). A heat stability assay suggests it may be mildly unstable (Blackwell 1971). Further, biochemical characterization indicates that the variant protein oligomerizes through formation of intermolecular disulfide bonds (Fablet 2003, Rai 2002), although these oligomers display normal binding kinetics to carbon monoxide (Fablet 2003). However, as the full functional and clinical effects of this variant have not been characterized, the clinical significance of the p.Gly84Cys variant is uncertain at this time. References: HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Blackwell RQ et al. Hemoglobin Ta-Li: 83 Gly leads to Cys. Biochim Biophys Acta. 1971 Sep 28;243(3):467-74. PMID: 5129589. Fablet C et al. Stable octameric structure of recombinant hemoglobin alpha(2)beta(2)83 Gly-->Cys. Protein Sci. 2003 Apr;12(4):690-5. PMID: 12649426. Rai DK et al. Characterization of the elusive disulfide bridge forming human Hb variant: Hb Ta-Li beta83 (EF7)Gly --> Cys by electrospray mass spectrometry. J Am Soc Mass Spectrom. 2002 Feb;13(2):187-91. PMID: 11838022. -

HEMOGLOBIN TA-LI 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.;T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.92	.;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.6	H;H;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.7	D;.;.;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.016	D;.;.;.
Polyphen		0.96	D;D;.;.
Vest4		0.64
MutPred		0.65		Gain of methylation at K83 (P = 0.0231);Gain of methylation at K83 (P = 0.0231);Gain of methylation at K83 (P = 0.0231);Gain of methylation at K83 (P = 0.0231);
MVP		0.92
MPC		0.25
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.78
gMVP		0.82

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: rs33930385; hg19: chr11-5247872;