11-5226930-C-T

Position:

chr11-5226930-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000335295.4(HBB):c.92G>A(p.Arg31Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000479 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HBB
ENST00000335295.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.79

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 18 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 ENST00000335295.4

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-G is described in ClinVar as [Pathogenic]. Clinvar id is 15234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 11-5226930-C-T is Pathogenic according to our data. 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. Variant chr11-5226930-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.92G>A	p.Arg31Lys	missense_variant, splice_region_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.92G>A	p.Arg31Lys	missense_variant, splice_region_variant	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251362

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135840

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726670

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:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 26, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 02, 2021	The HBB c.92G>A (p.Arg31Lys) variant (also known as IVS-I (-1) or Codon 30 (G>A)) changes the last nucleotide of exon 1 and is located at the exon 1-intron 1 junction. It is predicted to interfere with proper beta-globin mRNA splicing and may affect normal beta-globin mRNA production. This variant is associated with beta (0)-thalassemia (PMID: 2577233 (1989), and PMID: 19254853 (2009)). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 18, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.92G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2915972, 18056002, 27828729). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 36337). This variant is also known as p.Arg30Lys, codon 30 (G‚ÜíA) , IVS-I (-1). This missense change has been observed in individuals with beta thalassemia (PMID: 10815781, 26410419). This variant is present in population databases (rs33960103, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 31 of the HBB protein (p.Arg31Lys). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 12, 2022	The IVS-I (-1) or codon 30 (G->A) variant (HBB: c.92G>A; p.Arg31Lys, also known as Arg30Lys when numbered from the mature protein, HbVar ID: 816, rs33960103) is reported in the compound heterozygous state in individuals affected with beta (0) thalassemia (see link to HbVar, Kalaydjieva 1989, Maazoun 2016, Muniz 2000). This variant is also reported in ClinVar (Variation ID: 36337), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the last nucleotide of exon 1 and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by severely weakening the nearby canonical donor splice site. Additionally, another variant at this nucleotide (Hb Monroe variant, c.92G>C; p.Arg31Thr, HbVar ID: 290) has been reported in individuals with beta (0) thalassemia, is shown to affect splicing, and is considered pathogenic (Vidaud 1989). Based on available information, the p.Arg31Lys variant is considered to be likely pathogenic. References: Link to HbVar for IVS-I (-1): https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=816 Kalaydjieva L et al. The molecular basis of beta thalassaemia in Bulgaria. J Med Genet. 1989 Oct;26(10):614-8. PMID: 2577233. Maazoun F et al. Symptomatic extramedullary haematopoiesis in beta-thalassemia: A retrospective single centre study. Rev Med Interne. 2016 Jan;37(1):5-12. French. PMID: 26410419. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 May;64(1):7-14. PMID: 10815781. Vidaud M et al. A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1041-5. PMID: 2915972. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

T;T;.;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

.;T;T;T

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

N;.;.;N

REVEL

Pathogenic

0.90

Sift

Uncertain

0.012

D;.;.;D

Sift4G

Uncertain

0.035

D;.;.;.

Polyphen

0.99

D;D;.;.

Vest4

0.65

MutPred

0.81

Gain of ubiquitination at R31 (P = 0.03);Gain of ubiquitination at R31 (P = 0.03);Gain of ubiquitination at R31 (P = 0.03);Gain of ubiquitination at R31 (P = 0.03);

MVP

0.97

MPC

0.23

ClinPred

0.90

GERP RS

5.2

Varity_R

0.75

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.43

Position offset: 16

DS_DL_spliceai

0.64

Position offset: 0

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