ENST00000485743.1:c.316G>C

Variant names:

• chr11-5226576-C-G
• rs33945777
• ENST00000485743.1:c.316G>C

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000485743.1(HBB):​c.316G>C​(p.Val106Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V106A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB ENST00000485743.1 missense
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 26 ACMG points.

• PS1: Transcript ENST00000485743.1 (HBB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 619686
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 9 uncertain in ENST00000485743.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226575-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-5226576-C-G is Pathogenic according to our data. Variant chr11-5226576-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226576-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.315+1G>C		splice_donor_variant, intron_variant	Intron 2 of 2	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.315+1G>C		splice_donor_variant, intron_variant	Intron 2 of 2	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461262 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726980

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:2

Jan 15, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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

- -

not provided Pathogenic:1

Sep 14, 2021

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in insertion of the first 47 nucleotides of intron 2 between exons 2 and 3 or with exon 2 skipping and introduces a new termination codon (PMID: 7151176). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 189128). This variant is also known as IVS-II-1 (G->C). Disruption of this splice site has been observed in individuals with beta thalassemia (PMID: 2446680, 8718703, 27263053, 28391758). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 2 of the HBB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs33945777; hg19: chr11-5247806;