11-5227021-T-C

Position:

• chr11-5227021-T-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.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: HBB NM_000518.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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-C is Pathogenic according to our data. Variant chr11-5227021-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 439140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227021-T-C is described in Lovd as [Pathogenic]. Variant chr11-5227021-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.1A>G	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	c.1A>G	p.Met1?	start_lost	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152170 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome Cov.: 26

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74482

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 01, 2023	The HBB c.1A>G; p.Met1? variant (rs34563000), also known as Met1Val or initiation codon ATG->GTG, is reported in the literature in several heterozygous individuals affected with beta-thalassemia minor (Liu 2011, Perea 2004, HbVar database and references therein). 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>G variant is considered to be pathogenic. References: Link to c.1A>G in HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=775 Liu SC et al. Molecular lesion frequency of hemoglobin gene disorders in Taiwan. Hemoglobin. 2011;35(3):228-36. Perea FJ et al. Molecular spectrum of beta-thalassemia in the Mexican population. Blood Cells Mol Dis. 2004 Sep-Oct;33(2):150-2. -

Hemoglobinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 09, 2018

Variant summary: HBB c.1A>G alters the initiation codon (i.e. ATG coding for methionine to a triplet GTG coding for valine, so the predicted protein level name would be p.Met1Val), and it is expected that the next available, downstream ATG codon will be used as a translational start site. However, as it is out of frame (located at codons 21-22), this would result in a frameshift followed by an early termination (at the next in-frame stop codon 118 nucleotides downstream), likely leading to a missing/non-functional protein product (Hattori 1991). Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245874 control chromosomes. The c.1A>G variant has been reported in the literature in multiple individuals in the heterozygous state causing Beta Thalassemia Minor (e.g. Hattori 1991, Huisman 1997, Ohba 1997, Perea 2004, Liu 2011), however it is expected that in homozygosity and/or compound heterozygosity with a severe variant, this variant is likely to cause the BTHAL MJR phenotype. Other changes affecting the initiation codon (such as: c.2T>G (p.Met1Arg), c.2T>C (p.Met1Thr), c.3G>A (p.Met1Ile)) have also been found in HBB patients (source: HGMD). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T;T;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-2.1	N;.;.;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.039	D;.;.;.
Polyphen		0.54	P;P;.;.
Vest4		0.98
MutPred		0.61		Loss of glycosylation at P6 (P = 0.1583);Loss of glycosylation at P6 (P = 0.1583);Loss of glycosylation at P6 (P = 0.1583);Loss of glycosylation at P6 (P = 0.1583);
MVP		0.68
ClinPred		0.88	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.72

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;