Genetic Variant ENST00000647020.1:c.-138C>A (chr11-5227159-G-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

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

The ENST00000647020.1(HBB):c.-138C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000905 in 552,662 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: 0.0000090 ( 0 hom. )

Consequence

HBB
ENST00000647020.1 5_prime_UTR

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1O:1

Conservation

PhyloP100: 1.75

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:

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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 11-5227159-G-T is Pathogenic according to our data. Variant chr11-5227159-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227159-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.-138C>A		upstream_gene_variant		ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.-138C>A		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000905

AC:

AN:

552662

Hom.:

Cov.:

AF XY:

0.00000669

AC XY:

AN XY:

298996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000518

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000486

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000330

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:4Other:1

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Mar 27, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-138C>A variant in HBB (also known as -88C>A) has been reported in the homozygous and compound heterozygous state in numerous individuals with Beta Thalassemia (selected publications: Rund 1991 PMID: 1986379, Atroshi 2021 PMID: 34794358, Hassan 2014 PMID: 24880717, Turner 2016 PMID: 27756326, Ozkinay 2015 PMID: 26076395, El-Shanshory 2014 PMID: 25408857, Baysal 2011 PMID: 22074124, Sirdah 2013 PMID: 23321370, Vetter 1997 PMID: 9163586). It has been reported in ClinVar (Variation ID 393701) but was absent from large population databases. This variant lies in a known transcription binding site (CACCC box) where other clinically significant HBB variants (such as c.-140C>T, c.-138C>T, c.-137C>G and c.-137C>T) have been identified. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PS4, PM1. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided

Pathogenic:3

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 individuals with Œ≤-thalassemia intermedia (PMID: 9163586, 21232998, 22180324, 25408857, 26076396). It has also been observed to segregate with disease in related individuals. This variant is also known as -88C>A in literature. ClinVar contains an entry for this variant (Variation ID: 393701). For these reasons, this variant has been classified as Pathogenic. -

Dec 07, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-138C>A variant (also known as -88C>A) not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant reduces the binding of transcription factors and causes decreased transcription of the beta-globin gene. In the published literature, the variant has been reported in individuals with beta(+)-thalassemia (PMIDs: 26948378 (2017), 26076395 (2015), 23321370 (2013), 20437613 (2010), 1986379 (1991)). -

Jan 23, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemoglobinopathy

Pathogenic:1

Nov 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.-138C>A is located in the untranscribed region upstream of the HBB gene region. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant lies in a known transcription binding site (CACCC box) where other HBB variants (such as c.-140C>T, c.-138C>T, c.-137C>G and c.-137C>T) are known to be pathogenic for BTHAL ITMD. The variant was absent in 30972 control chromosomes (gnomAD). The variant, c.-138C>A, has been reported in the literature in multiple individuals affected with Beta Thalassemia (Rund_1991, El-Shanshory_2014, Baysal_2011, Sirdah_2013). 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beta-plus-thalassemia

Pathogenic:1

Jan 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Uncertain:1

Jan 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.64

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