11-5226723-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_000518.5(HBB):​c.169G>A​(p.Gly57Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G57R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

HBB
NM_000518.5 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.57
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-5226722-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HBBNM_000518.5 linkc.169G>A p.Gly57Ser missense_variant 2/3 ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.169G>A p.Gly57Ser missense_variant 2/31 NM_000518.5 ENSP00000333994.3 P68871

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152074
Hom.:
0
Cov.:
32
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
GnomAD4 exome
Cov.:
36
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74402
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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 15, 2022Variant summary: HBB c.169G>A (p.Gly57Ser) results in a non-conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251448 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.169G>A has been reported as a VUS in the literature when identified as part of a newborn screening study in eight heterozygous individuals from Angola who were presumably unaffected by Hemoglobinopathy (e.g. Borges_2019). These report(s) do not provide unequivocal conclusions about the association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 22, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJan 08, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
0.74
DANN
Benign
0.75
DEOGEN2
Benign
0.054
T;T;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.086
N
LIST_S2
Uncertain
0.86
.;D;D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Uncertain
0.68
D;D;D;D
MetaSVM
Uncertain
0.075
D
MutationAssessor
Benign
1.5
L;L;.;.
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-2.6
D;.;.;D
REVEL
Uncertain
0.62
Sift
Benign
0.11
T;.;.;T
Sift4G
Benign
0.15
T;.;.;.
Polyphen
0.0030
B;B;.;.
Vest4
0.53
MutPred
0.72
Gain of disorder (P = 0.0676);Gain of disorder (P = 0.0676);Gain of disorder (P = 0.0676);Gain of disorder (P = 0.0676);
MVP
0.87
MPC
0.039
ClinPred
0.44
T
GERP RS
-10
Varity_R
0.20
gMVP
0.69

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: rs33935983; hg19: chr11-5247953; API