Variant 11-5227020-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000518.5(HBB):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,946 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HBB
NM_000518.5 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.93

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_000518.5 (HBB) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5227020-A-G is Pathogenic according to our data. Variant chr11-5227020-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227020-A-G is described in Lovd as [Pathogenic]. Variant chr11-5227020-A-G 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.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1441946

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718728

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 21, 2015	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 04, 2014	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2022	The HBB c.2T>C (p.Met1Thr) variant (also known as Initiation Codon T>C) disrupts in the translation initiation codon of the HBB mRNA and is predicted to interfere with HBB protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is associated with beta-zero thalassemia (PMIDs: 25849334 (2015), 25806420 (2015), 12368169 (2002), 9101288 (1997)). 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	Nov 24, 2023	The HBB c.2T>C; p.Met1? variant (also known as Initiation codon ATG>ACG; rs33941849, HbVar ID: 776) is reported in the literature in individuals affected with beta-thalassemia or beta-thalassemia trait (Jankovic 1990, Molchanova 1998, Muniz 2000, Najmabadi 2002, HbVar database). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical translation initiation codon and is predicted to result in an aberrant or absent protein. Taken together, this variant is considered pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Jankovic L et al. An initiation codon mutation as a cause of a beta-thalassemia. Hemoglobin. 1990;14(2):169-76. PMID: 2272840. Molchanova TP et al. Historical note: the beta-thalassemia allele in the noble Russian family Lermontov is identified as the ATG-->ACG change in the initiation codon. Hemoglobin. 1998;22(3):283-286. PMID: 9629504. 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;64(1):7-14. PMID: 10815781. Najmabadi H et al. Rare and unexpected mutations among Iranian beta-thalassemia patients and prenatal samples discovered by reverse-hybridization and DNA sequencing. Haematologica. 2002;87(10):1113-1114. PMID: 12368169. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 12, 2021	Disruption of the initiator codon has been observed in individual(s) with HBB-related conditions (PMID: 2272840, 9163586, 25849334, 29379553). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HBB protein in which other variant(s) (p.Glu7Lys) have been determined to be pathogenic (PMID: 20301551, 23297836, 26372199, 27117572). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 36310). This variant is also known as CD1 (ATG-ACG). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the HBB mRNA. The next in-frame methionine is located at codon 56. -

Beta zero thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1998

- -

Beta-thalassemia, lermontov type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1998

- -

Beta-thalassemia HBB/LCRB

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Dec 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;T;.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Uncertain

0.75

MutationTaster

Benign

1.0

PROVEAN

Uncertain

-3.1

D;.;.;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;.;.;D

Sift4G

Pathogenic

0.0010

D;.;.;.

Polyphen

0.98

D;D;.;.

Vest4

0.87

MutPred

0.60

Gain of glycosylation at M1 (P = 0.0042);Gain of glycosylation at M1 (P = 0.0042);Gain of glycosylation at M1 (P = 0.0042);Gain of glycosylation at M1 (P = 0.0042);

MVP

0.86

ClinPred

0.96

GERP RS

5.2

Varity_R

0.87

gMVP

0.75

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