chr11-5225701-A-T

Position:

chr11-5225701-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000518.5(HBB):c.341T>A(p.Val114Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,998 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 1.68

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.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_000518.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.341T>A	p.Val114Glu	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.341T>A	p.Val114Glu	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1 linkuse as main transcript	c.341T>A	p.Val114Glu	missense_variant	3/3			P1
HBB	ENST00000475226.1 linkuse as main transcript	n.273T>A		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1 linkuse as main transcript	c.*157T>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

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:

0.000192

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:

0.0000199

AC:

AN:

251270

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

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

AF:

0.00000616

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	The Hb New York variant (HBB: c.341T>A; p.Val114Glu, also known as Val113Glu when numbered from the mature protein, HbVar ID: 491) is reported in the heterozygous state in individuals with no associated hematological symptoms, and did not affect clinical symptoms when occurring in-trans with beta thalassemia or hemoglobin E, or when coinherited with alpha thalassemia trait (Chaibunruang 2018, Ranney 1967, Todd 1980, HbVar database and references therein). However, this variant is reported to contribute to a clinically significant sickling disorder in individuals who also carry the hemoglobin S allele (Calder 2012, McFarlane 2011). This variant is reported in ClinVar (Variation ID: 15286), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 114 is highly conserved, and results in a mildly unstable variant protein and reduced oxygen affinity (HbVar database and references therein). Based on available information, the Hb New York variant is considered likely pathogenic for sickling disease when found with HbS, although there is no evidence that it is disease-associated alone or in trans with a beta-thalassemia variant. References: Link to HbVar for HB New York: https://globin.bx.psu.edu/hbvar/menu.html Calder D et al. Sickle retinopathy in a person with hemoglobin s/new york disease. Case Rep Genet. 2012;2012:136582. PMID: 23346429. Chaibunruang A et al. Molecular Characteristics of Hb New York (B113(G15)Val?Glu, HBB: c.341T>A) in Thailand. Hemoglobin. 2018 Jan;42(1):11-15. PMID: 29464999. McFarlane A et al. A novel sickling hemoglobinopathy. N Engl J Med. 2011 Oct 20;365(16):1548-9. PMID: 22010933. Ranney HM et al. Haemoglobin New York. Nature. 1967 Mar 4;213(5079):876-8. PMID: 6030043. Todd D et al. Globin chain synthesis in haemoglobin New York (beta 113 replaced by glutamic acid). Br J Haematol. 1980 Dec;46(4):557-64. PMID: 7437334. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2022	Reported in unrelated patients with features of sickle cell trait; however, these patients also harbored the c.20A>T common variant (McFarlane et al., 2011; Calder et al., 2012); Also observed in patients referred for carrier screening and have normal hemoglobin testing (Lin et al., 2013; van Zwieten et al., 2014; Lou et al., 2014; Huang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb New York or Hb Kaohsiung; This variant is associated with the following publications: (PMID: 24200101, 24099628, 1428942, 12403232, 28865746, 24055728, 19631632, 18432506, 1634358, 25089872, 31980563, 29626415, 36053226, 22010933, 19429541, 30837609, 29464999, 28143837, 24985555, 23346429, 23383304) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2023	- -

not specified

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1980	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 27, 2021	Variant summary: HBB c.341T>A (p.Val114Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 630098 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00051 vs 0.011), allowing no conclusion about variant significance. Compound heterozygotes of c.341T>A and a beta thalassmia mutation have been reported in the literature in individuals affected with sickling disorder symptoms (McFarlane_2011). However, similar compound heterozygotes have been reported in patients without significant clinical symptoms (Zeng_1982, Lee_2008). In addition, compound heterozygotes of c.341T>A and an alpha-thalassemia allele have also been reported in patients without significant clinical symptoms (Ranney_1967, Chaibunruang_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

0.17

Eigen_PC

Benign

-0.0044

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.0

D;.

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.034

D;.

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.73

Gain of catalytic residue at V114 (P = 0.0981);Gain of catalytic residue at V114 (P = 0.0981);

MVP

0.90

MPC

0.24

ClinPred

0.89

GERP RS

2.4

Varity_R

0.80

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