11-5226592-A-T

Variant names:

• chr11-5226592-A-T
• rs34013622
• NM_000518.5:c.300T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000518.5(HBB):​c.300T>A​(p.Asp100Glu) 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 1,461,854 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.247

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 11-5226592-A-T is Pathogenic according to our data. Variant chr11-5226592-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 917854.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.300T>A	p.Asp100Glu	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.300T>A	p.Asp100Glu	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Erythrocytosis, familial, 6 Pathogenic:1

Nov 01, 2019

Unidade de Eritropatologia e Metabolismo do Ferro, Centro Hospitalar e Universitário de Coimbra

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

The Asp100Glu variant in HBB is a high oxygen affinity hemoglobin described first in members of a Portuguese family. The altered functional properties of this variant likely result from the inability to form a hydrogen bond between beta-chain aa 100Glu and alpha-chain aa 43Tyr; such a bond is formed in deoxy Hb A between the normally occurring beta 100Asp and alpha 43Tyr. The affected members have a distinct erythrocytosis with high hemoglobin levels. -

not specified Uncertain:1

Mar 22, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.300T>A (p.Asp100Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.300T>A, (also known as Asp99Glu or Hb Coimbra) is a known high oxygen affinity hemoglobin variant, and is reported in several heterozygotes, who were mostly asymptomatic and had compensatory erythrocytosis found in routine blood tests (e.g. Tamagnini_1991, Bento_2013, Oliveira_2018). To our knowledge, no homozygous occurrences or compound heterozygosity with pathogenic HBB variants were reported, therefore no clear conclusions about association of the variant with Hemoglobinopathy can be made. Publications reported experimental evidence evaluating samples from heterozygous carriers, and demonstrated that the variant resulted in an increase in oxygen affinity (Tamagnini_1991, Jorge_2018), but no differences in Bohr effect were found (Jorge_2018). One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic for Erythrocytosis. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	0.083
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.3	H;H;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.5	D;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.010	D;.;.
Polyphen		0.74	P;P;.
Vest4		0.94
MutPred		0.93		Gain of ubiquitination at K96 (P = 0.0725);Gain of ubiquitination at K96 (P = 0.0725);Gain of ubiquitination at K96 (P = 0.0725);
MVP		0.96
MPC		0.072
ClinPred		0.98	D
GERP RS		-0.86
Varity_R		0.75
gMVP		0.91

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: rs34013622; hg19: chr11-5247822;