11-5227013-A-T

Variant names:

• chr11-5227013-A-T
• rs713040
• NM_000518.5:c.9T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000518.5(HBB):​c.9T>A​(p.His3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). 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. H3L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.886

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.9T>A	p.His3Gln	missense_variant	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.9T>A	p.His3Gln	missense_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251090 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135708

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455180 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724392

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Okayama variant (HBB: c.9T>A; p.His3Gln, also known as His2Gln when numbered from the mature protein, rs713040, HbVar ID: 220) is reported in the heterozygous state in individuals with with no hematological abnormalities (Harano 1983, van Zwieten 2014, see link to HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 15296), but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Functional analyses of the variant protein show normal stability and slightly increased oxygen affinity (see link to HbVar). Based on available information, this variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Harano T et al. Hemoglobin Okayama (beta 2 (NA 2) His replaced by Gln): a new 'silent' hemoglobin variant with substituted amino acid residue at the 2,3-diphosphoglycerate binding site. FEBS Lett. 1983 May 30;156(1):20-2. PMID: 6852251. van Zwieten R et al. Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones. Hemoglobin. 2014;38(1):1-7. PMID: 24200101. -

HEMOGLOBIN OKAYAMA 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	Benign	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	0.71
DANN	Benign	0.95
DEOGEN2	Benign	0.096	T;T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.71	.;T;T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M;M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.7	D;.;.;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0090	D;.;.;D
Sift4G	Benign	0.11	T;.;.;.
Polyphen		0.031	B;B;.;.
Vest4		0.64
MutPred		0.31		Gain of glycosylation at P6 (P = 0.108);Gain of glycosylation at P6 (P = 0.108);Gain of glycosylation at P6 (P = 0.108);Gain of glycosylation at P6 (P = 0.108);
MVP		0.60
MPC		0.034
ClinPred		0.18	T
GERP RS		-6.5
Varity_R		0.34
gMVP		0.47

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: rs713040; hg19: chr11-5248243;