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rs77121243

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_000518.5(HBB):c.20A>C(p.Glu7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

1
4
13

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 0.690
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 5 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 12 uncertain in NM_000518.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-5227003-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.37789398).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBBNM_000518.5 linkuse as main transcriptc.20A>C p.Glu7Ala missense_variant 1/3 ENST00000335295.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBBENST00000335295.4 linkuse as main transcriptc.20A>C p.Glu7Ala missense_variant 1/31 NM_000518.5 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458400
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
725786
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 08, 2023Variant summary: HBB c.20A>C (p.Glu7Ala), also known as the Hb G Makassar variant, results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251180 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, c.20A>C has been reported in the literature in several healthy homozygous and heterozygous individuals, who were exclusively of Thai and Indonesian descent and identified as having abnormal hemoglobin bands through HPLC analysis, but were found to have normal blood test results and no clinical abnormalities (e.g., Blackwell_1970, Viprakasit_2002, Thongnoppakhun_2009, Saechan_2010, Sangkitporn_2002). In a compound heterozygous individual where a pathogenic variant was identified in trans, the individual only displayed a Beta-thalassemia minor phenotype (e.g., Viprakasit_2002). At least one publication reports experimental evidence evaluating an impact on protein function, showing that c.20A>C represents a benign variant that rescued the disease phenotype in a humanized mouse sickle cell model (e.g., Newby_2021). The following publications have been ascertained in the context of this evaluation (PMID: 1363932, 5509617, 34079130, 20838957, 12188388, 19460936, 12403489). One ClinVar submitter (evaluation after 2014) has cited the variant as other (in reference to Blackwell_1970 in which the variant was identified in a healthy heterozygous individual). Based on the evidence outlined above, the variant was classified as likely benign. -
HEMOGLOBIN G (MAKASSAR) Other:1
other, no assertion criteria providedliterature onlyOMIMDec 12, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Benign
7.9
DANN
Benign
0.80
DEOGEN2
Benign
0.080
T;T;.;T
Eigen
Benign
-0.96
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.19
N
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.38
T;T;T;T
MetaSVM
Benign
-0.60
T
MutationAssessor
Benign
1.3
L;L;.;.
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-3.7
D;.;.;D
REVEL
Uncertain
0.50
Sift
Benign
0.35
T;.;.;T
Sift4G
Benign
0.58
T;.;.;.
Polyphen
0.0
B;B;.;.
Vest4
0.79
MutPred
0.42
Loss of disorder (P = 0.0675);Loss of disorder (P = 0.0675);Loss of disorder (P = 0.0675);Loss of disorder (P = 0.0675);
MVP
0.94
MPC
0.035
ClinPred
0.077
T
GERP RS
0.15
Varity_R
0.26
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs334; hg19: chr11-5248232; API