11-5226954-T-G

Position:

chr11-5226954-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The ENST00000335295.4(HBB):c.68A>C(p.Glu23Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E23G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HBB
ENST00000335295.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4O:4

Conservation

PhyloP100: 1.78

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 Likely_pathogenic. Variant got 6 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 ENST00000335295.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226955-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.68A>C	p.Glu23Ala	missense_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.68A>C	p.Glu23Ala	missense_variant	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251294

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135798

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461520

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727102

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:4Other:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1Benign:2

Pathogenic, flagged submission	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb G-Coushatta; This variant is associated with the following publications: (PMID: 23001606, 9048934, 34426522, 6033745, 29717566, 31553106, 19429541, 25572187, 6021187, 3115700, 18619001, 23806067, 5658717, 30568544, 34766575, 5791015, 31300739, 37188672, 14081243, 721611, 2703366, 28865746, 10081986) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 29, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 10, 2023

Variant summary: HBB c.68A>C (p.Glu23Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 676170 control chromosomes (gnomAD and publications). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Hemoglobinopathy (8.4e-05 vs 0.011), allowing no conclusion about variant significance. c.68A>C has been reported in the literature in healthy Native American, East Asian, Turkish, Egyptian, and Sri Lankan individuals in the heterozygous or homozygous state, suggesting that the variant is benign (e.g. Schneider_1964, Ohba_1978, Cao_1987, Li_1990, Hergersberg_2008, HbVar database). It has also been found to co-occur in cis and in trans with pathogenic beta-thalassemia variants (e.g. c.93-21G>A, IVS-1-1, G>A, and IVS-I-5) in patients, however in these cases it was believed to have little to no clinical impact (e.g. Hergersberg_2008, Koseler_2013, Perera_2015) . These data indicate that the variant is unlikely to be associated with disease. Additionally, a functional study has shown the variant to have normal oxygen equilibrium characteristics, and heat denaturation and isopropanol tests on hemolysates did not reveal instability of the hemoglobin, suggesting that the variant has a neutral effect on protein function (Ohba_1978). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=1)/likely benign (n=2), VUS (n=1), pathogenic (n=1) or other (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

beta Thalassemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

HEMOGLOBIN G (COUSHATTA)

Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

HEMOGLOBIN G (HSIN-CHU)

Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

HEMOGLOBIN G (TAEGU)

Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

HEMOGLOBIN G (SASKATOON)

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

0.051

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.038

T;T;.;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.071

.;T;T;T

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.3

L;L;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.5

N;.;.;D

REVEL

Uncertain

0.57

Sift

Benign

0.082

T;.;.;T

Sift4G

Benign

0.34

T;.;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.67

MutPred

0.67

Loss of catalytic residue at E23 (P = 0.0407);Loss of catalytic residue at E23 (P = 0.0407);Loss of catalytic residue at E23 (P = 0.0407);Loss of catalytic residue at E23 (P = 0.0407);

MVP

0.91

MPC

0.043

ClinPred

0.082

GERP RS

2.8

Varity_R

0.22

gMVP

0.67

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

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