Variant chr11-5226978-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000518.5(HBB):c.44T>C(p.Leu15Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 3.64

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.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.44T>C	p.Leu15Pro	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.44T>C	p.Leu15Pro	missense_variant	1/3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461162

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726914

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 23, 2024	The HBB c.44T>C (p.Leu15Pro) variant (also known as Hb Saki) has been reported to be unstable, with normal clinical presentation in heterozygotes (PMID: 998617 (1976), and HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)). The frequency of this variant in the general population, 0.0000066 (1/152206 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 01, 2021	The Hb Saki variant (HBB: c.44T>C; p.Leu15Pro, also known as Leu14Pro when numbered from the mature protein, rs33935445) is reported in the literature in multiple clinically healthy heterozygous individuals (see link to HbVar and references therein). This variant has also been reported in compound heterozygosity with an unspecified variant in an individual with beta-thalassemia intermedia (HbVar). This variant does not separate from Hb A during electrophoresis (see link to HbVar). This variant has also been reported along with Hb S in a clinically healthy individual (HbVar). This variant is reported as unstable, but with normal oxygen affinity, Bohr effect, and cooperativity (HbVar). This variant is reported in ClinVar (Variation ID: 15341) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 15 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.822). Due to limited information, the clinical significance of the p.Leu15Pro variant is uncertain at this time. References: Link to Hb Var database for Hb Saki: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=244&.cgifields=histD -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 25, 2021

Variant summary: HBB c.44T>C (p.Leu15Pro) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. This variant is also known in the literature as Hb-Saki. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251236 control chromosomes. c.44T>C has been reported in the literature in at least 2 families (e.g. Milner_1976, Beuzard_1975). At least 2 heterozygous individuals with the variant had no clinical symptoms reported, while a patient with the variant in compound heterozygosity with an unspecified mutation had a history of anemia, enlarged spleen, and an episode of severe hemolysis (e.g. Milner_1976). Evaluation of red cells from individuals with the variant showed mild instability (e.g. Milner_1976). Two other ClinVar submitters (evaluation after 2014) cited the variant as uncertain significance (n=1) and "other" (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

beta Thalassemia

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 21, 2019

- -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 23, 2022

- -

HEMOGLOBIN SAKI

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

0.92

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.080

T;T;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.84

.;T;T;T

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.0

H;H;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.1

D;.;.;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;.;.;D

Sift4G

Uncertain

0.0040

D;.;.;.

Polyphen

1.0

D;D;.;.

Vest4

0.92

MutPred

0.77

Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);

MVP

0.85

MPC

0.30

ClinPred

0.99

GERP RS

4.1

Varity_R

0.98

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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