11-5227019-C-T

Position:

• chr11-5227019-C-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.3G>A​(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: not found (cov: 33)
• Consequence: HBB NM_000518.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.72

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 11-5227019-C-T is Pathogenic according to our data. Variant chr11-5227019-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227019-C-T is described in Lovd as [Pathogenic]. Variant chr11-5227019-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 04, 2017

- -

Beta zero thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1993

- -

Dominant beta-thalassemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 21, 2022

Variant summary: HBB c.3G>A alters the initiation codon (therefore the predicted protein level name is p.Met1Ile) and is expected to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The variant was absent in 251128 control chromosomes (gnomAD). c.3G>A has been reported in the literature in multiple individuals in the heterozygous state, who had hematologic findings characteristic for Beta Thalassemia Minor (Saba_1991, Landin_1995, Vetter_1997), in addition, one of the reported heterozygous individuals had child(ren) with transfusion-dependent thalassemia (Hussain_2017). These data indicate that the variant in homozygosity and/or compound heterozygosity with a severe variant, is likely to cause the BTHAL MJR phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting the initiation codon (e.g. c.1A>G, c.2T>G, c.2T>C) have been classified as pathogenic by our laboratory. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

beta Thalassemia Pathogenic:1

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

Feb 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T;T;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.61	D
PROVEAN	Benign	-2.1	N;.;.;N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;.;.;D
Sift4G	Uncertain	0.020	D;.;.;.
Polyphen		0.97	D;D;.;.
Vest4		0.99
MutPred		0.62		Gain of catalytic residue at M1 (P = 0.0305);Gain of catalytic residue at M1 (P = 0.0305);Gain of catalytic residue at M1 (P = 0.0305);Gain of catalytic residue at M1 (P = 0.0305);
MVP		0.78
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.72
gMVP		0.71

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: rs33930702; hg19: chr11-5248249;