rs35939489

Positions:

• chr11-5226692-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000518.5(HBB):​c.200A>C​(p.Lys67Thr) 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K67E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 2.47

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 Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226693-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 11-5226692-T-G is Pathogenic according to our data. Variant chr11-5226692-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.200A>C	p.Lys67Thr	missense_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.200A>C	p.Lys67Thr	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 09, 2024	The HBB c.200A>C (p.Lys67Thr) variant has been reported in the published literature in a family with mild anemia (PMID: 3429244 (1987)). Functional studies demonstrate this variant decreased oxygen affinity by 50%, increases structural rigidity, and results in a mildly unstable hemoglobin which is damaging to proper protein function (PMIDs: 3429244 (1987), 10085107 (1991), 12881463 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 18, 2021	The Hb Chico variant (HBB: c.200A>C; p.Lys67Thr, also known as Lys66Thr when numbered from the mature protein rs35939489) has been reported in individuals with mild anemia (HbVar database and references therein). Functional characterizations indicate that Hb Chico has reduced oxygen affinity and might be mildly unstable (Bonaventura 1991, HbVar and references therein). However, the phenotype of this variant in the presence of other alpha globin variants is unknown. This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Lys67Asn, Lys67Ile, Lys67Glu) have been reported in heterozygous individuals with mild to moderate anemia and are considered disease causing (HbVar and references therein). The lysine at residue 66 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.838). Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database for Hb Chico: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=367 Link to HbVar database for Hb Ulm: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1191&.cgifields=histD Link to HbVar database for Hb Vigo: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=3136&.cgifields=histD Link to HbVar database for Hb I-Toulouse: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=366&.cgifields=histD Bonaventura J et al. (1991) Involvement of the distal histidine in the low affinity exhibited by Hb Chico (Lys beta 66----Thr) and its isolated beta chains. J Biol Chem. 266(34):23033-40. -

HEMOGLOBIN CHICO 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	0.51
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T;T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.2	M;M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.6	D;.;.;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Benign	0.17	T;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.76
MutPred		0.94		Gain of ubiquitination at K66 (P = 0.0442);Gain of ubiquitination at K66 (P = 0.0442);Gain of ubiquitination at K66 (P = 0.0442);Gain of ubiquitination at K66 (P = 0.0442);
MVP		0.98
MPC		0.089
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.62
gMVP		0.81

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: rs35939489; hg19: chr11-5247922;