Variant chr11-5227071-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000518.5(HBB):c.-50A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,232,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

HBB
NM_000518.5 5_prime_UTR

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 0.523

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]

HBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5227071-T-G is Pathogenic according to our data. Variant chr11-5227071-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 36292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227071-T-G is described in Lovd as [Pathogenic]. Variant chr11-5227071-T-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.-50A>C		5_prime_UTR_variant	1/3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.-50A>C		5_prime_UTR_variant	1/3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

249250

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

134686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000852

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000732

AC:

AN:

1079866

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

555048

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:

0.000995

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000367

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 14, 2023	The HBB c.-50A>C variant (rs33915217, HbVarID: 770), also known as CAP +1 (A>C), is reported in the literature in individuals affected with beta thalassemia either in the homozygous state or in trans to another pathogenic HBB variant (Garewal 2007, Wong 1987, HbVar database). In the heterozygous state, the c.-50A>C variant is considered “silent” and is associated with only minor hematological abnormalities, if any (Khattak 2012). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 36292), and is found in the South Asian population with an allele frequency of 0.085% (26/30,504 alleles) in the Genome Aggregation Database. This variant occurs in the 5' untranslated region at a nucleotide that is moderately conserved. Based on available information, the c.-50A>C variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Garewal G et al. The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians. Eur J Haematol. 2007 Nov;79(5):417-21. PMID: 17900295. Khattak SA et al. Prevalence of various mutations in beta thalassaemia and its association with haematological parameters. J Pak Med Assoc. 2012 Jan;62(1):40-3. PMID: 22352100. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6. PMID: 3683554. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2023	This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs34305195, gnomAD 0.08%). This variant has been observed in individuals with beta thalassemia (PMID: 19254853, 22335963, 27263053). This variant is also known as the "Cap+1" or "Cap site+1" variant. ClinVar contains an entry for this variant (Variation ID: 36292). Studies have shown that this variant alters HBB gene expression (PMID: 3683554). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2021	The frequency of this variant in the general population, 0.00085 (26/30504 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant is associated with mild beta (+)-thalassemia (PMID: 3683554 (1987), 22335963 (2012), 27263053 (2016), 32722952 (2020), 33491330 (2021)). Based on the available information, this variant is classified as pathogenic. -

beta Thalassemia

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2017	Variant summary: The HBB c.-50A>C (also known as CAP +1 A>C) variant involves the alteration of a non-conserved nucleotide, which lies in the CAP-site from where transcription starts. One in silico tool predicts a damaging outcome for this variant. This variant was found in 12/119792 control chromosomes at a frequency of 0.0001002, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). The variant was reported in numerous Beta Thalassemia patients individuals in the literature. Taken together, this variant is classified as pathogenic. -

Beta-plus-thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 26, 1987

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.79

La Branchor

0.65

BranchPoint Hunter

4.0

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over