11-5226708-T-C

Position:

• chr11-5226708-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000518.5(HBB):​c.184A>G​(p.Lys62Glu) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K62M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 0.406

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, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.184A>G	p.Lys62Glu	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.184A>G	p.Lys62Glu	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: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 05, 2024

Variant summary: HBB c.184A>G (p.Lys62Glu, also known as Lys61Glu, Hb N-Seattle) results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.184A>G has been reported in the literature in individuals affected with Anemia but also found in individuals without clinical symptoms (example, Jones_1968, Schroeder_1982). These report(s) do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. At least one publication reports experimental evidence evaluating an impact on protein function using blood samples from a heterozygous donor without clinical presentation, however, does not allow convincing conclusions about the variant effect (Jones_1968). The following publications have been ascertained in the context of this evaluation (PMID: 5637049, 7092797). ClinVar contains an entry for this variant (Variation ID: 15280). Based on the evidence outlined above, the variant was classified as uncertain significance. -

beta Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 31, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

The Hb N-Seattle (HBB: c.184A>G; p.Lys62Glu, also known as Lys61Glu when numbered from the mature protein, rs33995148, HbVar: 353) has been reported in a heterozygous blood donor with normal clinical presentation. However, its phenotype when found with other pathogenic globin variants is uncertain, and has not been described in the literature. The Hb N-Seattle hemoglobin variant is stable, and comprises half of the total hemoglobin in the individual (HbVar database and references therein). It is listed in ClinVar (Variation ID: 15280), but absent from 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: 0.699). Although Hb N-Seattle has not been associated with clinical symptoms or hemoglobin abnormalities, there is insufficient information to determine its clinical significance with certainty. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html -

HEMOGLOBIN N (SEATTLE) 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	0.46
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T;T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	4.1	H;H;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;.;.;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Benign	0.097	T;.;.;.
Polyphen		0.90	P;P;.;.
Vest4		0.58
MutPred		0.87		Loss of methylation at K62 (P = 0.013);Loss of methylation at K62 (P = 0.013);Loss of methylation at K62 (P = 0.013);Loss of methylation at K62 (P = 0.013);
MVP		0.97
MPC		0.079
ClinPred		0.93	D
GERP RS		2.7
Varity_R		0.76
gMVP		0.79

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: rs33995148; hg19: chr11-5247938;