11-5226619-C-G

Position:

• chr11-5226619-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000518.5(HBB):​c.273G>C​(p.Glu91Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,876 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E91G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.764

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 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226621-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 11-5226619-C-G is Pathogenic according to our data. Variant chr11-5226619-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 15311.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5226619-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.273G>C	p.Glu91Asp	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.273G>C	p.Glu91Asp	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461876 Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemoglobinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 06, 2023

Variant summary: HBB c.273G>C (p.Glu91Asp) 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 251422 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This amino acid change (also known as Pierre-Benite or beta Glu90Asp) can be caused by c.273G>T as well as c.273G>C and is known as a high oxygen affinity hemoglobin variant that has been reported in the literature in heterozygous individuals affected with erythrocytosis/polycythaemia (example, Baklouti_1988, Beard_2001, Percy_2009, Oliviera_2018). These data indicate that the variant is very likely to be associated with dominant familial erythrocytosis while not providing unequivocal conclusions about association of the variant with Beta Thalassemia or a Hemglobinopathy. To our knowledge, no homozygous or compound heterozygous occurrence of the variant with pathogenic HBB variants have been reported. At least one publication reports experimental evidence evaluating a sample from a heterozygous patient, finding indication of increased oxygen affinity (Beard_2001). The following publications have been ascertained in the context of this evaluation (PMID: 19734427, 11843890, 3384709, 29790589). One submitter has provided an entry for this variant to ClinVar after 2014 without a clinical significance assessment. Based on the evidence outlined above, the variant was classified as pathogenic. -

HEMOGLOBIN PIERRE-BENITE 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	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.099	D
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.8	D;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;.;.
Sift4G	Benign	0.30	T;.;.
Polyphen		0.035	B;B;.
Vest4		0.85
MutPred		0.90		Loss of ubiquitination at K96 (P = 0.1435);Loss of ubiquitination at K96 (P = 0.1435);Loss of ubiquitination at K96 (P = 0.1435);
MVP		0.95
MPC		0.13
ClinPred		0.95	D
GERP RS		2.3
Varity_R		0.66
gMVP		0.70

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: rs35002698; hg19: chr11-5247849;