Variant chr11-5226939-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_000518.5(HBB):c.83C>A(p.Ala28Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 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 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. A28V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:2

Conservation

PhyloP100: 7.26

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226940-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 11-5226939-G-T is Pathogenic according to our data. Variant chr11-5226939-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 15386.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.83C>A	p.Ala28Asp	missense_variant	1/3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.83C>A	p.Ala28Asp	missense_variant	1/3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460980

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726882

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 13, 2020

The variant has been reported as an unstable beta globin variant. Individuals heterozygous for this variant have been reported to present with hemolytic anemia (PMID 952960 (1976), 3240605 (1998), 27686852 (2016)). In addition, this variant was reported as a de novo mutation in two individuals with hemolytic anemia (PMID 24904938 (2014), 8330973 (1993)). Therefore, this variant is classified as pathogenic. -

HEMOGLOBIN VOLGA

Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

HEMOGLOBIN DRENTHE

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

0.98

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;.;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.4

H;H;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.7

D;.;.;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.;.;D

Sift4G

Pathogenic

0.0

D;.;.;.

Polyphen

1.0

D;D;.;.

Vest4

0.88

MutPred

0.81

Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);

MVP

0.95

MPC

0.24

ClinPred

1.0

GERP RS

5.2

Varity_R

0.95

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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