GeneBe

rs33925391

Variant names:
GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.
+11 Pathogenic
-7
-6
-1
0
+5
+6
+9
+10
B
LB
VUS
LP
P
 The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3

The NM_000518.5(HBB):c.380T>G (p.Val127Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000205 (AC=3) in the gnomAD database across 1,461,774 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★★). ClinVar reports functional evidence for this variant: "SCV001361819: The variant protein was demonstrated to be unstable under certain in vitro conditions (Pagano_1991, Divoky_1992).". A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.V127E: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 15201) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V127A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 15106); p.V127L: other (ClinVar VariationId 15597, 0 stars); p.V127= (synonymous): Likely_benign (ClinVar VariationId 1142046, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

7
6
6

Clinical Significance

Uncertain significance reviewed by expert panel P:8U:1

Conservation

PhyloP100: 0.0220

Publications

18 publications found
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 Gene-Disease associations (from GenCC):
  • dominant beta-thalassemia
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, Natera
  • erythrocytosis, familial, 6
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • hemoglobin M disease
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, Ambry Genetics
  • unstable hemoglobin disease
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • beta thalassemia
    Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women's Health
  • beta-thalassemia and related diseases
    Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
  • beta-thalassemia HBB/LCRB
    Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
  • sickle cell disease
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, Natera
  • sickle cell disease and related diseases
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • Heinz body anemia
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
  • hereditary persistence of fetal hemoglobin
    Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
  • delta-beta-thalassemia
    Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
  • hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • beta-thalassemia intermedia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • beta-thalassemia major
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin C disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin C-beta-thalassemia syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin E disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin E-beta-thalassemia syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-beta-thalassemia disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin c disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin d disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • sickle cell-hemoglobin E disease syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000518.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 points.

PS3
Well-established functional study supports damaging effect (PS3); SCV001361819: The variant protein was demonstrated to be unstable under certain in vitro conditions (Pagano_1991, Divoky_1992).
PM1
UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 131 pathogenic, 51 benign rare missense variants (OR vs. background: 12.8).; ±8 AA neighbourhood: 11 pathogenic, 5 benign (OR vs. background: 10.5).
PM2
Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000116 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00265) — PM2 moderate.
PM5
Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.V127E: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 15201); Other variants at the same amino acid residue (not pathogenic): p.V127A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 15106); p.V127L: other (ClinVar VariationId 15597, 0 stars); p.V127= (synonymous): Likely_benign (ClinVar VariationId 1142046, 1 star)
PP3
Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000518.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
HBB
NM_000518.5
MANE Select
c.380T>Gp.Val127Gly
missense
Exon 3 of 3NP_000509.1P68871

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
HBB
ENST00000335295.4
TSL:1 MANE Select
c.380T>Gp.Val127Gly
missense
Exon 3 of 3ENSP00000333994.3P68871
HBB
ENST00000647020.1
c.380T>Gp.Val127Gly
missense
Exon 3 of 3ENSP00000494175.1P68871
HBB
ENST00000883533.1
c.380T>Gp.Val127Gly
missense
Exon 4 of 4ENSP00000553592.1P68871

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461774
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727212
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111918
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.542
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

Case/control cohorts

Cohort
Cases
Controls
Epi25
(Epilepsy)
1 / 41958AF: 0.0000238334
1 / 66888AF: 0.0000149504

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions
Significance:Uncertain significance
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
3
-
-
not provided (3)
2
-
-
beta Thalassemia (2)
1
1
-
Beta-thalassemia HBB/LCRB (2)
1
-
-
Beta thalassemia intermedia (1)
1
-
-
Hemoglobinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.50
FATHMM_MKL
Benign
0.21
N
LIST_S2
Uncertain
0.86
D
M_CAP
Pathogenic
0.34
D
MetaRNN
Uncertain
0.72
D
MetaSVM
Uncertain
0.27
D
MutationAssessor
Pathogenic
3.9
H
PhyloP100
0.022
PrimateAI
Benign
0.29
T
PROVEAN
Uncertain
-2.8
D
REVEL
Pathogenic
0.67
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.014
D
Varity_R
0.50
popEVE
Benign
-3.8
VESM-3B
Benign
-9.2
FuncVEP CTI
Pathogenic
0.74
AlphaGenome AVI
Uncertain
10
GPN-Star LLR
-4.7
GPN-Star score
4.7
Mutation Taster
=2/98
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2
Pangolin (max)
Benign
0.0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

Other links and lift over

dbSNP: rs33925391;
hg19: chr11-5246892;
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