11-5227020-A-G

Variant names:

• chr11-5227020-A-G
• rs33941849
• NM_000518.5:c.2T>C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 90 pathogenic variants. Next in-frame start position is after 56 codons. Genomic position: 5226726. Lost 0.374 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441946 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 718728

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.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:4

Sep 04, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Apr 21, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:3

Jul 20, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Disruption of the initiator codon has been observed in individual(s) with HBB-related conditions (PMID: 2272840, 9163586, 25849334, 29379553). 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. -

Jul 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Beta zero thalassemia Pathogenic:1

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Beta-thalassemia, lermontov type Pathogenic:1

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Beta-thalassemia HBB/LCRB Pathogenic:1

Dec 18, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
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	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.75	D
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	D
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

Other links and lift over

dbSNP: rs33941849; hg19: chr11-5248250;