rs281865423

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000518.5(HBB):c.295G>A(p.Val99Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,862 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V99G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.20

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:

HBB (HGNC:):

HBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226596-A-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 11-5226597-C-T is Pathogenic according to our data. Variant chr11-5226597-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226597-C-T is described in Lovd as [Pathogenic]. Variant chr11-5226597-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.295G>A	p.Val99Met	missense_variant	2/3	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.295G>A	p.Val99Met	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251394

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

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:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemoglobinopathy

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2019	Variant summary: HBB c.295G>A (p.Val99Met; also known as Hb Koln) results in a conservative amino acid change located in the Globin domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes (gnomAD). c.295G>A has been reported in the literature in heterozygous and compound heterozygous individuals presenting with clinical symptoms of Hemoglobinopathy and was observed to co-segregate with disease in an autosomal dominant manner (Chan_2010, Galacteros_1989, Huang_2011, Miller_1971). The occurrence of unstable hemoglobin and the presence of increased levels of reticulocytosis and Heinz bodies in those carrying the variant was described by a few of these studies. Several reports described the variant as the most common unstable hemoglobin (e.g. Coleman_1995). These data indicate that the variant is very likely to be associated with disease. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	The Hb Koln variant (HBB: c.295G>A; p.Val99Met, also known as Val98Met when numbered from the mature protein, rs33933298, HbVar ID: 448) is reported in the literature in multiple families diagnosed with mild hemolytic anemia, including several de novo cases, and is associated with Heinz body formation and splenomegaly (Hutchinson 1964, Jackson 1967, Jones, 1967, Landin 1994, Miller 1971, Stamatoyannopoulos 1981, HbVar database and references therein). Clinical symptoms are present in heterozygous individuals, and the variant co-segregates with disease in an autosomal dominant manner (Hutchinson 1964, Jackson 1967). In addition, this variant has been found in an individual with a beta(0) thalassemia variant who was reported to have almost pure Hb Koln in red blood cells and hemolytic anemia, but did not require blood transfusions or splenectomy (Galacteros 1989). This variant is listed in ClinVar (Variation ID: 15241), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Functional analyses of the variant protein show decreased stability and an increase in the formation of inclusion bodies in red blood cells (Jones 1967, Miller 1971). Based on available information, this variant is considered to be pathogenic. References: HbVar link for HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Galacteros F et al. Hemoglobin Köln occurring in association with a beta zero thalassemia: hematologic and functional consequences. Blood. 1989 Jul;74(1):496-500. Hutchinson HE et al. Hereditary Heinz-body anaemia, thrombocytopenia, and haemogloblinopathy (Hb Koeln) in a Glasgow family. Br Med J. 1964 Oct 31;2(5417):1099-103. Jackson JM et al. A West Australian family with a haemolytic disorder associated with haemoglobin Koln. Br J Haematol. 1967 Jul;13(4):474-81. Jones RV et al. Koln haemoglobinopathy. Further data and a comparison with other hereditary Heinz body anaemias. Br J Haematol. 1967 May;13(3):394-408. Landin B et al. Haemoglobin Köln as de novo mutations in Sweden: diagnosis by PCR and specific enzymatic cleavage. Eur J Haematol. 1994 Mar;52(3):156-61. Miller DR et al. Hemoglobin Koln disease occurring as a fresh mutation: erythrocyte metabolism and survival. Blood. 1971 Dec;38(6):715-29. -

beta Thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Heinz body anemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;H;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.6

D;.;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;.

Polyphen

1.0

D;D;.

Vest4

0.97

MutPred

0.94

Gain of ubiquitination at K96 (P = 0.1062);Gain of ubiquitination at K96 (P = 0.1062);Gain of ubiquitination at K96 (P = 0.1062);

MVP

0.95

MPC

0.25

ClinPred

0.99

GERP RS

5.2

Varity_R

0.80

gMVP

0.96

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