rs193922561

chr11-5225822-C-Gchr11-5225822-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000518.5(HBB):c.316-96G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000531 in 1,291,074 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: HBB NM_000518.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.240

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-5225822-C-G is Benign according to our data. Variant chr11-5225822-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36321.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.316-96G>C		intron_variant		ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.316-96G>C		intron_variant		1	NM_000518.5	P1
HBB	ENST00000647020.1	c.316-96G>C		intron_variant				P1
HBB	ENST00000633227.1	c.*132-96G>C		intron_variant, NMD_transcript_variant		3
HBB	ENST00000475226.1	n.248-96G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

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: 0.000750

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000551 AC: 628 AN: 1138794 Hom.: 0 AF XY: 0.000548 AC XY: 319 AN XY: 581698

Gnomad4 AFR exome AF: 0.000184

Gnomad4 AMR exome AF: 0.0000229

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: 0.000736

Gnomad4 OTH exome AF: 0.000361

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74470

Gnomad4 AFR AF: 0.000168

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: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2023	The HBB c.316-96G>C variant, to the best of our knowledge, has not been reported in the published literature. The frequency of this variant in the general population, 0.00045 (7/15430 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 splicing yielded predictions that this variant does not affect HBB mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 19, 2022

Variant summary: HBB c.316-96G>C is located at a position not widely known to affect splicing. 4/4 computational 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 0.00038 in 150934 control chromosomes (gnomAD v3.1.2), predominantly at a frequency of 0.00075 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00038 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.316-96G>C in individuals affected with Hemoglobinopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed this variant since 2014: one classified the variant as uncertain significance and one as likely benign. There are several reported disease variants described within this intron (e.g. c.316-3C>A, c.316-7C>A, c.316-12T>C, c.316-14T>G, c.316-106C>G, c.316-146T>G, and c.316-197C>T) and some have been shown to generate an alternative splice-site, suggesting this deep intronic variant should be interpreted with caution. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.8
Dann	Benign	0.41

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: rs193922561; hg19: chr11-5247052;