11-5225632-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000518.5(HBB):​c.410G>A​(p.Gly137Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,996 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

9
5
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:5

Conservation

PhyloP100: 1.22
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-5225632-C-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HBBNM_000518.5 linkuse as main transcriptc.410G>A p.Gly137Asp missense_variant 3/3 ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkuse as main transcriptc.410G>A p.Gly137Asp missense_variant 3/31 NM_000518.5 ENSP00000333994.3 P68871

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000119
AC:
3
AN:
251372
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
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
AF:
0.00000205
AC:
3
AN:
1461820
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152176
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
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
Alfa
AF:
0.0000979
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 24, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 02, 2024- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 26, 2022Variant summary: HBB c.410G>A (p.Gly137Asp) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251372 control chromosomes (gnomAD). c.410G>A has been reported in the literature as a clinically innocuous variant in individuals with mildly anemic phenotypes and also in co-occurrence among individuals with HbCS, Hb-H disease, and HbE/beta-thalassemia (e.g. Minnich_1965, Ingle_2004, Enoki_1989, Martinez_1984, Pagnier_1978, Sura_2007, Beneitez_2006, Fucharoen_2012, Svasti_2001, Chunpanich_2004, Rahbar_1992, Pillers_1992, Delacour_2016, Srivorakun_2014, Singha_2021). In particular, compound heterozygous individuals with Hb-Hope-HbS genotypes did not present with sickle cell disease phenotype (e.g. Ingle_2004). These data indicate that the variant is not strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Enoki_1989). The most pronounced variant effect results in reduced oxygen affinity. Three clinical diagnostic laboratories and OMIM have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Most classified the variant as benign/likely benign, and one laboratory classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria providedliterature onlyOMIMDec 12, 2017- -
Hb SS disease Pathogenic:1
Pathogenic, flagged submissionclinical testingBaylor Genetics-- -
Beta-thalassemia HBB/LCRB Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor Genetics-- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 08, 2017This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
beta Thalassemia Benign:1
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.42
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.099
T;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.81
.;T
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.5
M;M
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-2.8
D;.
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D;.
Sift4G
Benign
0.62
T;.
Polyphen
0.91
P;P
Vest4
0.84
MutPred
0.70
Loss of catalytic residue at V138 (P = 0.0525);Loss of catalytic residue at V138 (P = 0.0525);
MVP
0.86
MPC
0.28
ClinPred
0.97
D
GERP RS
4.7
Varity_R
0.77
gMVP
0.86

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: rs33949486; hg19: chr11-5246862; API