chr11-5227020-A-T

Position:

• chr11-5227020-A-T

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>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 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: 6.9e-7 (0 hom.)
• Consequence: HBB NM_000518.5 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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, 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-T is Pathogenic according to our data. Variant chr11-5227020-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227020-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.2T>A	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.2T>A	p.Met1?	start_lost	1/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441946 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 718728

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

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	Feb 18, 2019	Variant summary: HBB c.2T>A (p.Met1Lys) 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. Missense mutation of the initiation codon is widely regarded as deleterious (p.Met1Val, p.Met1Thr, and p.Met1Arg are internally classified as pathogenic). In the HBB gene, other changes at this codon are pathogenic and mutations in the initiation codon are expected to cause severe BTHAL disease. The nearest downstream ATG is codon 55. It is possible that translation of the mutant mRNA initiates from the single in-frame initiation codon (codon 55) and produces a truncated beta-chain that is highly unstable. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245874 control chromosomes (gnomAD). c.2T>A has been reported in the literature in heterozygous state (once as a de novo occurrence), in 3 individuals, at least two of them presenting with beta-thalassemia intermedia (Vasseur_2017, Lacan_2005, Waye_1997). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 31, 2018

The variant disrupts the natural start codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T;T;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.75	D
PROVEAN	Uncertain	-3.1	D;.;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		0.99	D;D;.;.
Vest4		0.89
MutPred		0.63		Gain of ubiquitination at M1 (P = 0.023);Gain of ubiquitination at M1 (P = 0.023);Gain of ubiquitination at M1 (P = 0.023);Gain of ubiquitination at M1 (P = 0.023);
MVP		0.87
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;