dbSNP rs33971634: HBB:p.Gln128* (chr11-5225660-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000518.5(HBB):c.382C>T(p.Gln128*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,252 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

HBB
NM_000518.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.01

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]

HBB links:

ENSG00000285498 (HGNC:):

ENSG00000285498 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5225660-G-A is Pathogenic according to our data. Variant chr11-5225660-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1705074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225660-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.382C>T	p.Gln128*	stop_gained	Exon 3 of 3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.382C>T	p.Gln128*	stop_gained	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251276

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dominant beta-thalassemia

Pathogenic:1

Mar 17, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.382C>T (p.Gln128X, also reported as p.Glu127X) is located in exon 3 (i.e. in the last exon) of the HBB gene. The current variant results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a C-terminal truncation, removing a part of the 147 amino acid long protein. A truncation downstream of this position has been classified as pathogenic for dominant B-THAL by our laboratory. The variant allele was found at a frequency of 4e-06 in 251276 control chromosomes (gnomAD). c.382C>T has been reported in the literature in multiple individuals affected with considerable variation in phenotype (even within the same famlily), ranging from mild, clinically asymptomatic anemia to severe hemolytic anemia with splenomegaly (e.g. Hall_1991, Van Weel_1999, Prehu_2005), where occasionally the presence of Heinz bodies was also noted. These data indicate that the variant is likely associated with disease. A publication reported experimental evidence and demonstrated that substantial amounts of mutant beta-mRNA were present in individuals carrying the variant, thus demonstrating that the variant does not result in nonsense mediated decay (NMD), suggesting that a truncated protein product can be produced, which might also explain the presence of the occasionally reported Heinz bodies (Hall_1994). 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 pathogenic for dominant B-THAL. -

not provided

Pathogenic:1

Jun 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.382C>T (p.Gln128*) variant creates a premature stop codon in the last exon of the beta-globin gene. An RNA study indicates the mutant mRNA transcript is not degraded by nonsense-mediated decay, and is predicted to result in the production of a truncated protein lacking the terminal 20 amino acids of the beta-globin chain (PMID: 8161774 (1994)). This variant is associated with dominant beta-thalassemia in which heterozygous carriers present with varying phenotype, ranging from clinically asymptomatic anemia to thalassemia intermedia (PMIDs: 9450794 (1998), 8161774 (1994), 1958498 (1991)). In addition, this variant has been reported as a de novo variant in a heterozygous individual with microcytic hypochromic hemolytic anemia and splenomegaly (PMID: 10569730 (1999)). Previous names for this variant include Codon 127 C>T. Based on the available information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

Vest4

0.74

GERP RS

4.7

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over