rs63751128

Positions:

• chr11-5225487-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000518.5(HBB):​c.*111A>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 0.00000591 in 1,015,192 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: HBB NM_000518.5 3_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 1.45

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5225487-T-C is Pathogenic according to our data. Variant chr11-5225487-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 15488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225487-T-C is described in Lovd as [Pathogenic]. Variant chr11-5225487-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.*111A>G		3_prime_UTR_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.*111A>G		3_prime_UTR_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.*111A>G		3_prime_UTR_variant	3/3			P1
HBB	ENST00000633227.1	c.*371A>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	3
	ENST00000644706.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152242 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000464 AC: 4 AN: 862950 Hom.: 0 Cov.: 12 AF XY: 0.00000221 AC XY: 1 AN XY: 453340

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: 0.00000700

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74392

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:2 Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 02, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 04, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 18, 2022	This variant is located in the 3-prime-untranslated region and alters the polyadenylation signal. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant was reported to likely cause the inefficient cleavage and polyadenylation of the beta globin mRNA and was associated with beta(+) thalassemia (PMID: 2375910 (1990), 1856830 (1991), 8112743 (1994), 19205970 (2009), 26418075 (2015), 26956563 (2016), 35336809 (2022)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 1856830, 2375910). 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 AATGAA. ClinVar contains an entry for this variant (Variation ID: 15488). Studies have shown that this variant alters HBB gene expression (PMID: 3024968). For these reasons, this variant has been classified as Pathogenic. -

Hemoglobinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 22, 2019

Variant summary: HBB c.*111A>G is located in the untranslated mRNA region downstream of the termination codon that lies in the 'known' polyA tail signal (AATAAA) of HBB, and mutations in this region are known to reduce the synthesis of mRNA. Therefore, this variant is expected or likely to interfere with cleavage of transcript and addition of polyA tail, leading to an elongated transcript that is unstable (PMID: 4018033). 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 31396 control chromosomes (gnomAD). c.*111A>G has been reported in the literature in multiple individuals (compound heterozygous/heterozygous and homozygous) affected with Hemoglobinopathy. Patient who was homozygous for this variant had a mild, non-transfusion dependent thalassemia phenotype (Losekoot_1991). Jankovic et al report individuals who were heterozygous for this variant had rather mild + thalassaemia, but when present in combination with other more severe types of -thalassaemia variants could result in transfusion-dependent thalassaemia major or thalassaemia intermedia (Jankovic_1990). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Feb 01, 2024

- -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.82

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

Other links and lift over

dbSNP: rs63751128; hg19: chr11-5246717;