11-5226799-C-A

Position:

chr11-5226799-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000518.5(HBB):c.93G>T(p.Arg31Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense, splice_region

Scores

Splicing: ADA: 0.9987

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:6

Conservation

PhyloP100: 1.84

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 7 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000518.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226930-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.93G>T	p.Arg31Ser	missense_variant, splice_region_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.93G>T	p.Arg31Ser	missense_variant, splice_region_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152152

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:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251316

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000126

AC:

184

AN:

1461592

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727138

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:

0.00328

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000250

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74464

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:

0.00339

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000407

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2022	The Hb Tacoma variant (HBB: c.93G>T; p.Arg31Ser, also known as Arg30Ser when numbered from the mature protein, HbVar ID: 289, rs1135071) is reported in the literature in the heterozygous state in individuals with mild anemia or no symptoms (Deacon-Smith 1978, Idelson 1974, Landin 1993), and in one individual with Hb S who had sickle cell trait (Honig 1980). This variant is also reported in ClinVar (Variation ID: 15368) and is found in the Finnish European population with an allele frequency of 0.36% (90/25120 alleles) in the Genome Aggregation Database. The arginine at codon 31 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.947). This variant is the first nucleotide of the exon, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Functional analyses demonstrate a normal oxygen affinity but slight instability (Deacon-Smith 1978, Honig 1980). Due to conflicting information, the clinical significance of the Hb Tacoma variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Deacon-Smith RA and Lee-Potter JP. An unstable haemoglobin, Hb Tacoma beta30 (B12) arg leads to ser, detected at birth by the demonstration of red cell inclusions. J Clin Pathol. 1978 Sep;31(9):883-7. PMID: 711920. Honig GR et al. Two new sickle cell syndromes: HbS, Hb Camden, and alpha-thalassemia; and HbS in combination with Hb Tacoma. Blood. 1980 Apr;55(4):655-60. PMID: 7357091. Idelson LI et al. New unstable haemoglobin (Hb Moscva, beta24 (B4) Gly leads to Asp) found in the USSR. Nature. 1974 Jun 21;249(459):768-70. PMID: 4525423. Landin B and Jeppsson JO. Rare beta chain hemoglobin variants found in Swedish patients during HBA1c analysis. Hemoglobin. 1993 Aug;17(4):303-18. PMID: 8226093. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 18, 2023	The HBB c.93G>T (p.Arg31Ser) variant (also known as Hb Tacoma) has been reported to have normal oxygen affinity but slightly reduced stability (PMIDs: 31553106 (2020), 7357091 (1980), 5785231 (1969), 5869485 (1965)). Individuals who are heterozygous for this variant have normal presentations (PMID: 5869485 (1965)) or mild anemia (PMIDs: 34233561 (2021), 8226093 (1993), 3937827 (1985)). Co-occurrence of this variant with Hb S presented as clinically healthy (PMID: 7357091 (1980)), but in combination with a beta(+)-thalassemia variant resulted in moderate microcytic anemia (PMID: 10975446 (2000)). Additionally, an individual who was compound heterozygous for Hb Tacoma caused by a different nucleotide change (c.93G>C, p.Arg31Ser) and a HBB pathogenic variant associated with beta(0)-thalassemia is reported to have transfusion-dependent beta thalassemia (PMID: 9140720 (1997)). Analysis of this variant using bioinformatics tools indicates that the effect of this variant's amino acid change on protein structure and function is damaging, and it may also affect proper HBB mRNA splicing. Clinical correlation and genetic counseling are recommended. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 21, 2018	This sequence change replaces arginine with serine at codon 31 of the HBB protein (p.Arg31Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs1135071, ExAC 0.3%). This variant has been observed in individuals and families with elevated Hb A2 levels, but most individuals are either clinically unaffected or experience only mild anemia (PMID: 8226093, 4525423, 5869485, 3937827, 7357091). This variant is also known as Arg30Ser and Hb Tacoma in the literature. ClinVar contains an entry for this variant (Variation ID: 15368). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Pathogenic:1Uncertain:1

Pathogenic, flagged submission	literature only	OMIM	Feb 01, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 30, 2024	Variant summary: HBB c.93G>T (p.Arg31Ser) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site. One predicts the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00035 in 251316 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia (0.00035 vs 0.011), allowing no conclusion about variant significance. Hb Tacoma is used to describe the substitution of Arg-to-Ser at codon 31 (legacy codon 30) and can be due to either c.93G>T or c.93G>C. It has been reported in the literature in heterozygous individuals with no clinical or hematological abnormalities apart from mild anemia (Deacon-Smith_1978, Harano_1985, Moore_2021) and in one heterozygous individual who also carried Hb S and had normal hematological findings (Honig_1980). c.93G>T in particular was reported in heterozygous individuals with normal hematological findings in some of them and slight hemolytic anemia in others, while importantly it was also reported in a 12-year-old boy in compound heterozygosity with pathogenic variant c.93-21G>A and no signs of disease (Landin 1993, 2000). The variant was also found in multiuple homozygous individuals without clinical information (Kangastupa_2023). These reports do not provide unequivocal conclusions about association of the variant with Beta Thalassemia. Experimental evidence evaluating an impact on protein function demonstrate the variant to display in vitro instability, including a decreased alkaline Bohr effect and haem-haem interaction but normal oxygen affinity (Deacon-Smith_1978, Hayashi_1974). These data do not allow convincing conclusions about the variant effect The following publications have been ascertained in the context of this evaluation (PMID: 8226093, 6859036, 7357091, 711920, 3937827, 4407364, 10975446, 34233561, 36633442). ClinVar contains an entry for this variant (Variation ID: 15368). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Heinz body anemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

beta Thalassemia

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 16, 2021

- -

Beta-thalassemia HBB/LCRB

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Nov 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

.;T;T;T

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.084

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.2

D;.;.;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.020

D;.;.;D

Sift4G

Uncertain

0.029

D;.;.;.

Polyphen

1.0

D;D;.;.

Vest4

0.63

MutPred

0.87

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.99

MPC

0.26

ClinPred

0.33

GERP RS

4.2

Varity_R

0.89

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.020

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