11-5227021-T-G

Position:

• chr11-5227021-T-G

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.1A>C​(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.0000014 in 1,433,520 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBB NM_000518.5 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.81

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, 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 11-5227021-T-G is Pathogenic according to our data. Variant chr11-5227021-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 869231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227021-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.1A>C	p.Met1?	initiator_codon_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.1A>C	p.Met1?	initiator_codon_variant	1/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433520 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 715036

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2023	Variant summary: HBB c.1A>C (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next available downstream ATG codon, located at codons 21-22, would result in a frameshift leading to premature termination of translation at codons 60-61, likely resulting in a missing/non-functional protein product (Knott_2006). Alternatively, activation of the next downstream in-frame start codon (Met56) would result in a shortened protein missing the first 55 amino acids from the protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251128 control chromosomes (gnomAD). c.1A>C has been reported in the literature in the heterozygous state in at least two individuals presenting with beta-thalassemia minor/intermedia (e.g. Knott_2006, Rizo_2021). Thus, it is expected that in homozygosity and/or compound heterozygosity, this variant is likely to cause BTHAL MJR phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, missense mutation of the initiation codon is widely regarded as deleterious (p.Met1Val, p.Met1Thr, p.Met1Ile, and p.Met1Arg are internally classified as pathogenic). Thus, in the HBB gene, other changes in the initiation codon are expected to cause severe BTHAL disease. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 15, 2019

The HBB c.1A>C; p.Met1? variant is reported in the literature in an individual affected with microcytic anemia and diagnosed as a beta-thalassemia carrier (Knott 2006). This variant is absent from general population databases (Exome Variant Server, 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. Other variants that affect the HBB initiation codon have been reported in individuals with beta-thalassemia or microcytic anemia and are considered pathogenic (HbVar database and references therein). Based on available information, the c.1A>C variant is considered to be pathogenic. References: Link to HbVar database: http://globin.bx.psu.edu/ Knott M et al. Novel and Mediterranean beta thalassemia mutations in the indigenous Northern Ireland population. Blood Cells Mol Dis. 2006 Mar-Apr;36(2):265-8. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.032	T;T;.;T
Eigen	Benign	0.064
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.12	D
PROVEAN	Benign	-1.5	N;.;.;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.021	D;.;.;D
Sift4G	Uncertain	0.024	D;.;.;.
Polyphen		0.11	B;B;.;.
Vest4		0.87
MutPred		0.60		Loss of glycosylation at P6 (P = 0.2141);Loss of glycosylation at P6 (P = 0.2141);Loss of glycosylation at P6 (P = 0.2141);Loss of glycosylation at P6 (P = 0.2141);
MVP		0.52
ClinPred		0.67	D
GERP RS		5.2
Varity_R		0.49
gMVP		0.64

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: rs34563000; hg19: chr11-5248251;