11-5225648-G-T

Variant names:

• chr11-5225648-G-T
• rs33910209
• NM_000518.5:c.394C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP6

The NM_000518.5(HBB):​c.394C>A​(p.Gln132Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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. Q132E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:3
• Conservation: PhyloP100: 3.69

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]

ENSG00000285498 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225648-G-C is described in Lovd as [Pathogenic].
• BP6: Variant 11-5225648-G-T is Benign according to our data. Variant chr11-5225648-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15349.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.394C>A	p.Gln132Lys	missense_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.394C>A	p.Gln132Lys	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jan 03, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Sep 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.394C>A; Gln131Lys variant (rs33910209), commonly known as Hb Shelby, is a stable hemoglobin variant with normal oxygen affinity and has not been associated with any significant clinical symptoms in the heterozygous state or in combination with beta(0)-thalassemia, HbS, or HbC (Lutcher 1976, see link to HbVar and references therein). This variant is reported in ClinVar (Variation ID: 15349), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamine at codon 131 is highly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on available information, the Hb Shelby variant is considered to be likely benign. References: Link to HbVar for Hb Shelby: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=536&.cgifields=histD Lutcher CL et al. Hb Leslie, an unstable hemoglobin due to deletion of glutaminyl residue beta 131 (H9) occurring in association with beta0-thalassemia, HbC, and HbS. Blood. 1976 Jan;47(1):99-112. -

HEMOGLOBIN SHELBY Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN LESLIE Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN DEACONESS 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	.;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.020	D;.
Polyphen		0.16	B;B
Vest4		0.86
MutPred		0.73		Gain of methylation at Q132 (P = 0.0141);Gain of methylation at Q132 (P = 0.0141);
MVP		0.97
MPC		0.16
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.69
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: rs33910209; hg19: chr11-5246878;