chr11-5225733-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_000518.5(HBB):c.316-7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HBB
NM_000518.5 splice_region, intron

Scores

Splicing: ADA: 0.001439

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 0.474

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5225733-G-T is Pathogenic according to our data. Variant chr11-5225733-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551906.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=2}. Variant chr11-5225733-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73). . 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.316-7C>A		splice_region_variant, intron_variant	Intron 2 of 2	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBB	ENST00000335295.4 link	c.316-7C>A	splice_region_variant, intron_variant	Intron 2 of 2	1	NM_000518.5	ENSP00000333994.3	P68871
HBB	ENST00000647020.1 link	c.316-7C>A	splice_region_variant, intron_variant	Intron 2 of 2			ENSP00000494175.1	P68871
HBB	ENST00000475226.1 link	n.248-7C>A	splice_region_variant, intron_variant	Intron 1 of 1	2
HBB	ENST00000633227.1 link	n.*132-7C>A	splice_region_variant, intron_variant	Intron 2 of 2	3		ENSP00000488004.1	A0A0J9YWK4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251142

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000966

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:2

Jul 17, 2017

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 22, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Pathogenic:1Uncertain:1

Sep 27, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.[316-12T>C; 316-7C>A] complex variant is reported in the literature in multiple individuals as a very mild beta + thalassemia trait (Belisario 2015, Waye 2013), and has been found in trans with Hb S and Hb C in patients with clinical symptoms (Cross 2007, Belisario 2015, Waye 2013). The c.316-12T>C variant (rs755236703) is only observed on three alleles in the Genome Aggregation Database. The c.316-7C>A variant (rs34483965) is only observed on one allele in the Genome Aggregation Database. These are intronic variants in weakly conserved nucleotides, and computational analyses (Alamut v.2.11) predict that each variant may impact splicing by weakening the nearby canonical acceptor splice site, however, without mRNA analysis it is unclear how the combination of the two variants impact splicing. Based on available information, the c.[316-12T>C; 316-7C>A] complex variant is considered to be likely pathogenic. References: Belisario A et al. Very mild forms of Hb S/beta(+)-thalassemia in Brazilian children. Rev Bras Hematol Hemoter. 2015 37(3):198-201. Cross T et al. Sickle liver disease--an unusual presentation in a compound heterozygote for HbS and a novel beta-thalassemia mutation. Am J Hematol. 2007 82(9):852-4. Waye J et al. Mild beta(+)-thalassemia associated with two linked sequence variants: IVS-II-839 (T>C) and IVS-II-844 (C>A). Hemoglobin. 2013 37(4):378-86. -

Nov 12, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.316-7C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251142 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.316-7C>A (legacy name IVS-II-844C>A) in isolation has been reported in the literature as a compound heterozygous genotype with the HbS variant in at-least one individual with features of Sickle liver disease (Cross_2007) and as a complex allele in cis with c.316-12T>C (legacy name IVS-II-839T>C) in individuals affected with mild Beta Thalassemia (example, Waye_2013, Belisario_2013). As the possibility of incomplete genotyping in the earlier report (Cross_2007) cannot be entirely excluded, these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26041423, 31589614, 17565724, 23651435). ClinVar contains an entry for this variant (Variation ID: 551906). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Pathogenic:1Uncertain:1

Jul 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.316-7C>A variant has been reported in the published literature in an individual carrying Hb S with very mild clinical presentation (PMID: 17565724 (2007)). It is commonly found as a complex allele with the HBB c.316-12T>C variant, and the (c.316-12T>C; c.316-7C>A) complex allele is reported as being associated with mild beta(+)-thalassemia when it occurs in trans with Hb S or Hb C (PMID: 26041423 (2015), 23651435 (2013)).The frequency of this variant in the general population, 0.000004 (1/251142 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on HBB mRNA splicing yielded inconclusive findings (Alamut Visual (http://www.interactive-biosoftware.com/)). Based on the available information, we are unable to determine the clinical significance of this variant. -

Aug 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 551906). This variant is also known as IVS2-844C>A. This variant has been observed in individual(s) with HBB-related conditions (PMID: 17565724, 23651435, 26041423). In some individuals, it has been found in cis (on the same chromosome) with c.316-12T>C. In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). 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. -

Hb SS disease

Pathogenic:1

Baylor 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

-0.73

CADD

Benign

8.0

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.040

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