rs35256489

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000518.5(HBB):c.332T>C(p.Leu111Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,212 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L111L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 6.62

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_000518.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.898

PP5

Variant 11-5225710-A-G is Pathogenic according to our data. Variant chr11-5225710-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 15352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225710-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.332T>C	p.Leu111Pro	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBB	ENST00000335295.4 linkuse as main transcript	c.332T>C	p.Leu111Pro	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1 linkuse as main transcript	c.332T>C	p.Leu111Pro	missense_variant	3/3			P1
HBB	ENST00000475226.1 linkuse as main transcript	n.264T>C		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1 linkuse as main transcript	c.*148T>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251248

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000472

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2016	Variant summary: The HBB c.332T>C (p.Leu111Pro) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "damaging" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121382, which does not exceed the estimated maximal expected allele frequency for a pathogenic HBB variant of 1/89. The variant of interest has been reported in multiple affected individuals in both homozygous and compound heterozygous states. In addition, a reputable database cites the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 22, 2023	The HBB c.332T>C (p.Leu111Pro) pathogenic variant (also known as Hb Showa-Yakushiji) is reported in the published literature as a hyper unstable variant associated with beta thalassemia major and intermedia (PMIDs: 28670940 (2017), 27263053 (2016), 18495504 (2008), 15768552 (2005), 2634667 (1989), 2822177 (1987)). 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, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 03, 2023	The Hb Showa-Yakushiji variant (HBB: c.332T>C; p.Leu111Pro, also known as Leu110Pro when numbered from the mature protein, rs35256489, HbVar ID: 485) is reported to be a hyperunstable hemoglobin associated with beta(+) thalassemia (Colah 2008, Edison 2005, Kobayashi 1987, HbVar link). This variant is reported as pathogenic in ClinVar (Variation ID: 15352). It is only observed in one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 111 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.871). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Colah R et al. Hb Showa Yakushiji (beta 110 (G12) Leu-->Pro) in 3 families from Western India: first report on homozygous Hb Showa Yakushiji. Blood Cells Mol Dis. 2008 Sep-Oct;41(2):166-8. PMID: 18495504. Edison ES et al. Hb Showa-Yakushiji (beta110(G12)Leu-->Pro) in four unrelated patients from west Bengal. Hemoglobin. 2005;29(1):19-25. PMID: 15768552. Kobayashi Y et al. A novel globin structural mutant, Showa-Yakushiji (beta 110 Leu-Pro) causing a beta-thalassemia phenotype. Blood. 1987 Nov;70(5):1688-91. PMID: 2822177. -

Beta-Showa-Yakushiji thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Hb SS disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Beta-plus-thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

HEMOGLOBIN SHOWA-YAKUSHIJI

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

0.51

BayesDel_noAF

Pathogenic

0.50

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.92

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.3

D;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.67

Loss of stability (P = 0.0971);Loss of stability (P = 0.0971);

MVP

0.90

MPC

0.30

ClinPred

1.0

GERP RS

4.7

Varity_R

0.98

gMVP

0.97

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