Variant chr11-5225592-G-C 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.*6C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,770 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: 0.0000014 ( 0 hom. )

Consequence

HBB
NM_000518.5 3_prime_UTR

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 0.222

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 11-5225592-G-C is Pathogenic according to our data. Variant chr11-5225592-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225592-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78). . 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.*6C>G		3_prime_UTR_variant	3/3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBB	ENST00000335295 linkuse as main transcript	c.*6C>G	3_prime_UTR_variant	3/3	1	NM_000518.5	ENSP00000333994.3	P68871
HBB	ENST00000647020 linkuse as main transcript	c.*6C>G	3_prime_UTR_variant	3/3			ENSP00000494175.1	P68871
HBB	ENST00000633227.1 linkuse as main transcript	n.*266C>G	non_coding_transcript_exon_variant	3/3	3		ENSP00000488004.1	A0A0J9YWK4
HBB	ENST00000633227 linkuse as main transcript	n.*135C>G	3_prime_UTR_variant	2/2	3		ENSP00000488004.1	A0A0J9YWK4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251382

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135858

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727200

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000223

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Beta thalassemia intermedia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 20, 2022

Variant summary: HBB c.*6C>G is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in HBB causing Beta Thalassemia Intermedia (0.011), allowing no conclusion about variant significance. The variant c.*6C>G (aka. +1480T>G) has been reported in the literature in multiple individuals affected with Beta Thalassemia Intermedia (e.g. Maragoudaki_1998, Jankovic_1991, Aldemir_2014). These data indicate that the variant is very likely to be associated with disease. Publications also reported in vitro experimental evidence evaluating the variant impact, and demonstrated about 20-40% reduction in mRNA levels associated with variant compared to normal beta-globin alleles (Maragoudaki_1998, Sgourou_2002), while another study showed a slightly higher (1.1 fold) levels of expression than WT (Hino_2012). One reputable database has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2022

This variant is present in population databases (rs34809925, gnomAD 0.0009%). 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 has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 1777603, 9792288). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant does not significantly alter or has an unclear effect on HBB gene expression (PMID: 9792288, 22734587). ClinVar contains an entry for this variant (Variation ID: 393707). This variant is also known as term +6C>G or +1480C>G. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.5

DANN

Benign

0.79

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.

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