NM_000518.5:c.316-14T>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000518.5(HBB):​c.316-14T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,540 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 pathogenic (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HBB
NM_000518.5 intron

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.354
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5225740-A-C is Pathogenic according to our data. Variant chr11-5225740-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225740-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBBNM_000518.5 linkc.316-14T>G intron_variant Intron 2 of 2 ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.316-14T>G intron_variant Intron 2 of 2 1 NM_000518.5 ENSP00000333994.3 P68871
HBBENST00000647020.1 linkc.316-14T>G intron_variant Intron 2 of 2 ENSP00000494175.1 P68871
HBBENST00000475226.1 linkn.248-14T>G intron_variant Intron 1 of 1 2
HBBENST00000633227.1 linkn.*132-14T>G intron_variant Intron 2 of 2 3 ENSP00000488004.1 A0A0J9YWK4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461540
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727078
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:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Sep 10, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HBB c.316-14T>G variant (rs35703285, HbVar ID: 895), also known as IVS-II-837T>G, has been reported in the heterozygous state in individuals affected with microcytosis and hypochromia and is associated with an intermediate beta thalassemia phenotype when in combination with a beta(0) HBB variant on the opposite chromosome (Link to HbVar, Luo 2005, Nadkarni 2009, Sinha 2009, Varawalla 1991). It is reported in ClinVar (Variation ID: 36313) and absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Based on available information, this variant is considered pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Luo H et al. Patients with thalassemia in the United States. Blood. 2005 Jun 15;105(12):4896-7. PMID: 15933066. Nadkarni A et al. Hematological and molecular analysis of novel and rare beta-thalassemia mutations in the Indian population. Hemoglobin. 2009;33(1):59-65. PMID: 19205975. Sinha S et al. Profiling B-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. Hugo J. 2009 Dec;3(1-4):51-62. PMID: 21119755 Varawalla N et al. Rare beta-thalassaemia mutations in Asian indians. Br J Haematol. 1991 Dec;79(4):640-4. PMID: 1772786. -

Mar 02, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant is associated with beta(+)-thalassemia or beta(0)-thalassemia (PMID: 1772786 (1991), 18294253 (2008), 19205975 (2009), 22734501 (2012)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on HBB mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, this variant is classified as pathogenic. -

Sep 02, 2023
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed with a pathogenic variant in a patient with beta-thalassemia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Luo et al., 2005; Gupta et al., 2023); Reported as a common variant among individuals of South Indian background (Sinha et al., 2009; Baysham et al., 2012); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS-II-837 (T>G) using alternate nomenclature; This variant is associated with the following publications: (PMID: 30489691, 31766235, 1772786, 32412692, 23651435, 18294253, 22734501, 12709369, 15278762, 19254853, 23590658, 20437613, 19205975, 35620315, Gupta[article]2023, 33829933, 21119755, 15933066, 20230396) -

Oct 22, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with beta thalasemia (PMID: 15933066, 19205975, 22734501, 23590658). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS II:837 T>G. ClinVar contains an entry for this variant (Variation ID: 36313). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 07, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 24, 2020
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

beta Thalassemia Pathogenic:3
Aug 18, 2011
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing;curation

- -

Jul 26, 2022
Genetics and Molecular Pathology, SA Pathology
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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 Pathogenic:1
May 18, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
3.9
DANN
Benign
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.89
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.49
Position offset: -1
DS_AL_spliceai
0.89
Position offset: -14

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: rs35703285; hg19: chr11-5246970; API