dbSNP rs63750720: HBB:p.Leu4Pro (chr11-5227011-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000518.5(HBB):c.11T>C(p.Leu4Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L4V) 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

Not reported in ClinVar

Conservation

PhyloP100: 4.73

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 23 uncertain in NM_000518.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.11T>C	p.Leu4Pro	missense_variant	Exon 1 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.11T>C	p.Leu4Pro	missense_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1454532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724088

African (AFR)

AF:

0.00

AC:

AN:

33280

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105338

Other (OTH)

AF:

0.00

AC:

AN:

60140

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T;.;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.76

.;T;T;T

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

4.3

H;H;.;.

PhyloP100

4.7

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.7

D;.;.;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0060

D;.;.;D

Sift4G

Uncertain

0.010

D;.;.;.

Polyphen

0.65

P;P;.;.

Vest4

0.55

MutPred

0.57

Gain of glycosylation at T5 (P = 0.0303);Gain of glycosylation at T5 (P = 0.0303);Gain of glycosylation at T5 (P = 0.0303);Gain of glycosylation at T5 (P = 0.0303);

MVP

0.87

MPC

0.051

ClinPred

0.78

GERP RS

5.2

PromoterAI

0.033

Neutral

(source)

Varity_R

0.79

gMVP

0.97

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over