11-5226955-C-G

Position:

chr11-5226955-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_000518.5(HBB):c.67G>C(p.Glu23Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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. E23A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2O:1

Conservation

PhyloP100: 2.21

Variant links:

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]

HBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 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 chr11-5226954-T-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.2744512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.67G>C	p.Glu23Gln	missense_variant	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.67G>C	p.Glu23Gln	missense_variant	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251278

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135788

show subpopulations

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:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461552

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727112

show subpopulations

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:

0.000545

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2022	Reported in the homozygous and compound heterozygous state in patients with mild hemoglobinopathy (Thornburg et al., 2001; Bhat et al., 2012; Gupta et al., 2014); Also known as Hb D-Iran and p.E22Q; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20090224, 4715135, 8195010, 6434492, 7073867, 25023086, 20838957, 19783722, 4725603, 11196276, 17655708, 31553106, 20309827, 23543793, 25332633, 19429541) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 31, 2023

Variant summary: HBB c.67G>C (p.Glu23Gln) results in a conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251278 control chromosomes, predominantly at a frequency of 0.00049 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia (6e-05 vs 0.011), allowing no conclusion about variant significance. Hb D-Iran was identified in compound heterozygosity with Hb A with an asymptomatic clinical course, normal hemoglobin concentration, normal red blood cell morphology, absence of inclusion bodies, and a normal level of methemoglobin (Rahbar_1973). Hb D-Iran in combination with HbS causes benign sickle syndrome with normal red cell indices, normal growth, and no evidence of hemolysis or organomegaly (Serjeant_1982). A compound heterozygote for Hb D-Iran and - thal presented with hypochromic microcytic anemia with target cells and basophilic stippling with these finding being no different from those of a - thal carriers alone (Rohe_1973, Agrawal_2007, Bhat_2012, Mohanty_2017). Thornburg_2001 concluded that homozygous Hb D-Iran is a relatively benign condition with mild microcytic anemia, poikilocytosis, and minimal hemolysis based on the hematologic values, hemoglobin electrophoresis, peripheral blood smear, and clinical course. Hb D-Iran has no reported abnormalities in heat stability, oxygen equilibrium, intracellular 2,3 DPG, Bohr effect, or heme-heme interaction (Rohe_1973). The following publications have been ascertained in the context of this evaluation (PMID: 35287566, 17655708, 19783722, 23543793, 27207683, 8195010, 25332633, 9342003, 29519374, 33279152, 4715135, 4725603, 20090224, 20838957, 31553106, 7073867, 11196276, 20309827). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely benign (n=2) or VUS (n=1). Additional reports of presence in controls and in patients with alternate molecular basis of disease would be required to classify this variant as benign or likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign to emphasize the need for additional genotype-clinical phenotype correlations and that although the variant does not remarkably alter the clinical manifestations due to a known pathogenic variant in trans, the presence of some relatively mild clinical manifestations cannot be ruled out. -

HEMOGLOBIN D (IRAN)

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

Benign

0.093

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

T;T;.;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.31

.;T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.7

L;L;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

N;.;.;N

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

D;.;.;D

Sift4G

Benign

0.18

T;.;.;.

Polyphen

0.0010

B;B;.;.

Vest4

0.67

MutPred

0.67

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.88

MPC

0.047

ClinPred

0.062

GERP RS

-0.27

Varity_R

0.26

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over