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rs33930165

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000518.5(HBB):c.19G>T(p.Glu7Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,706 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E7E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HBB
NM_000518.5 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.63
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 370 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5227003-C-A is Pathogenic according to our data. Variant chr11-5227003-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 869230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-5227003-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBBNM_000518.5 linkuse as main transcriptc.19G>T p.Glu7Ter stop_gained 1/3 ENST00000335295.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBBENST00000335295.4 linkuse as main transcriptc.19G>T p.Glu7Ter stop_gained 1/31 NM_000518.5 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458706
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
725882
show subpopulations
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:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

beta Thalassemia Pathogenic:1
Pathogenic, no assertion criteria providedcurationThe ITHANET community portal, The Cyprus Institute of Neurology and GeneticsNov 25, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.30
Cadd
Pathogenic
36
Dann
Uncertain
0.99
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Benign
0.47
N
MutationTaster
Benign
1.0
A
Vest4
0.29
GERP RS
5.2

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs33930165; hg19: chr11-5248233; API