rs111851677

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000518.5(HBB):​c.93-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,607,692 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0055 ( 11 hom., cov: 32)
Exomes 𝑓: 0.00059 ( 7 hom. )

Consequence

HBB
NM_000518.5 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.112
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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 11-5226822-A-G is Benign according to our data. Variant chr11-5226822-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36340.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=3}. Variant chr11-5226822-A-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00551 (839/152216) while in subpopulation AFR AF = 0.0186 (774/41530). AF 95% confidence interval is 0.0175. There are 11 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
BS2
High Homozygotes in GnomAd4 at 11 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBBNM_000518.5 linkc.93-23T>C intron_variant Intron 1 of 2 ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.93-23T>C intron_variant Intron 1 of 2 1 NM_000518.5 ENSP00000333994.3 P68871

Frequencies

GnomAD3 genomes
AF:
0.00552
AC:
840
AN:
152098
Hom.:
11
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0187
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00301
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00528
GnomAD2 exomes
AF:
0.00139
AC:
349
AN:
250970
AF XY:
0.000922
show subpopulations
Gnomad AFR exome
AF:
0.0178
Gnomad AMR exome
AF:
0.00107
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.000979
GnomAD4 exome
AF:
0.000592
AC:
861
AN:
1455476
Hom.:
7
Cov.:
33
AF XY:
0.000509
AC XY:
369
AN XY:
724544
show subpopulations
Gnomad4 AFR exome
AF:
0.0189
AC:
630
AN:
33334
Gnomad4 AMR exome
AF:
0.00136
AC:
61
AN:
44710
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26102
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39654
Gnomad4 SAS exome
AF:
0.0000232
AC:
2
AN:
86146
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53406
Gnomad4 NFE exome
AF:
0.0000841
AC:
93
AN:
1106226
Gnomad4 Remaining exome
AF:
0.00116
AC:
70
AN:
60140
Heterozygous variant carriers
0
53
106
160
213
266
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
24
48
72
96
120
<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
AF:
0.00551
AC:
839
AN:
152216
Hom.:
11
Cov.:
32
AF XY:
0.00556
AC XY:
414
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.0186
AC:
0.0186371
AN:
0.0186371
Gnomad4 AMR
AF:
0.00301
AC:
0.00300654
AN:
0.00300654
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.000103
AC:
0.000102938
AN:
0.000102938
Gnomad4 OTH
AF:
0.00522
AC:
0.00522317
AN:
0.00522317
Heterozygous variant carriers
0
45
91
136
182
227
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00586
Hom.:
4
Bravo
AF:
0.00665
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

beta Thalassemia Uncertain:1Benign:2
Aug 18, 2011
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 25, 2019
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:curation

- -

Oct 14, 2022
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Benign:3
Dec 09, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 13, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Beta-thalassemia HBB/LCRB Benign:1
Aug 22, 2023
Mendelics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

HBB-related disorder Benign:1
Feb 19, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
2.4
DANN
Benign
0.65
Mutation Taster
=100/0
polymorphism

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: rs111851677; hg19: chr11-5248052; API