11-5227797-T-G

Variant names:

• chr11-5227797-T-G
• rs12289247
• ENST00000380315.2:c.-86-218A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The ENST00000380315.2(HBB):​c.-86-218A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 152,244 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0047 (2 hom., cov: 32)
• Consequence: HBB ENST00000380315.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.166
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• dominant beta-thalassemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia intermedia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia major

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-beta-thalassemia disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin c disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin d disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin E disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000380315.2	c.-86-218A>C		intron_variant	Intron 1 of 3	5		ENSP00000369671.2
ENSG00000298932	ENST00000759072.1	n.265+2069T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 710 AN: 152126 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00713

Gnomad OTH AF: 0.00621

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00466 AC: 710 AN: 152244 Hom.: 2 Cov.: 32 AF XY: 0.00434 AC XY: 323 AN XY: 74436

African (AFR) AF: 0.00159 AC: 66 AN: 41550

American (AMR) AF: 0.00562 AC: 86 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00293 AC: 31 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00713 AC: 485 AN: 68006

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00346 Hom.: 1

Bravo AF: 0.00470

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.7
DANN	Benign	0.50
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs12289247; hg19: chr11-5249027;