11-5225699-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM5BP4

The NM_000518.5(HBB):c.343C>A(p.Leu115Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,756 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 other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L115P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 0.412

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

dominant beta-thalassemia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
hemoglobin M disease
Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
beta thalassemia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
beta-thalassemia HBB/LCRB
Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
sickle cell disease and related diseases
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
erythrocytosis, familial, 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Heinz body anemia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
sickle cell disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
beta-thalassemia intermedia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
beta-thalassemia major
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
delta-beta-thalassemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin C disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin C-beta-thalassemia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin E disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin E-beta-thalassemia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-beta-thalassemia disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin c disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin d disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin E disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HBB links:

ENSG00000298932 (HGNC:):

ENSG00000298932 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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, 13 uncertain in NM_000518.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5225698-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.34306324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.343C>A	p.Leu115Met	missense_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.343C>A	p.Leu115Met	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251222

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111902

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000367

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN ZENGCHENG

Other:1

Dec 12, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.041

T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.85

.;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

0.41

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.4

N;.

REVEL

Uncertain

0.59

Sift

Benign

0.13

T;.

Sift4G

Benign

0.082

T;.

Polyphen

0.94

P;P

Vest4

0.40

MutPred

0.59

Loss of catalytic residue at L115 (P = 0.2844);Loss of catalytic residue at L115 (P = 0.2844);

MVP

0.53

MPC

0.068

ClinPred

0.15

GERP RS

0.28

Varity_R

0.23

gMVP

0.83

Mutation Taster

=40/60

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over