11-5226782-G-T

Position:

• chr11-5226782-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000335295.4(HBB):​c.110C>A​(p.Pro37His) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P37A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB ENST00000335295.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 6.33

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 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in ENST00000335295.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226783-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-5226782-G-T is Pathogenic according to our data. Variant chr11-5226782-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15578.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.110C>A	p.Pro37His	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.110C>A	p.Pro37His	missense_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Erythrocytosis, familial, 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

in vivo

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

Jan 14, 2020

The mutation CCT-CAT at codon 37 leads to the replacement of a proline residue by a histidine in the a1b2 contact of the Hb molecule and represents an important structural change causing a decreased molecular stability. This would predictably shift the equilibrium between deoxy-Hb and oxy-Hb slightly towards the oxy-Hb form. The oxygen equilibrium, measured with an automatic oxygenation apparatus was shifted leftward and the P50 was 17.0 mmHg (normal 26-27 mmHg) confirming a Hb with higher oxygen affinity than normal. This was the first observation of this hemoglobin variant that has been named Hb Vila Real after the city of the carrier place of birth. Hb Vila Real b36 (C2) Pro>His is the forth abnormal Hb found with an amino acid substitution at position 37 of the b-chain. The other three variants, Hb Linkoping, Hb North Chicago and Hb Sunnybrook also have increased oxygen affinity. -

Hypertrophic cardiomyopathy 26 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Sep 14, 2023

ACMG criteria used to clasify this variant: PP3_STR, PM2_SUP -

HEMOGLOBIN VILA REAL 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	.;T;T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.0	D;.;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.99
MutPred		0.93		Gain of catalytic residue at P37 (P = 0.0958);Gain of catalytic residue at P37 (P = 0.0958);Gain of catalytic residue at P37 (P = 0.0958);Gain of catalytic residue at P37 (P = 0.0958);
MVP		0.98
MPC		0.27
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.93

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: rs33993004; hg19: chr11-5248012;