11-5227540-G-A

Variant names:

• chr11-5227540-G-A
• rs10742584
• ENST00000380315.2:c.-47C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000380315.2(HBB):​c.-47C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 165,742 control chromosomes in the GnomAD database, including 75,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70092 hom., cov: 29)
  • Exomes 𝑓: 0.91 (5828 hom.)
• Consequence: HBB ENST00000380315.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.02
• Publications: 6 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• erythrocytosis, familial, 6

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

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet
• unstable hemoglobin disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: 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), Ambry Genetics, ClinGen
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Heinz body anemia

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-5227540-G-A is Benign according to our data. Variant chr11-5227540-G-A is described in ClinVar as Benign. ClinVar VariationId is 869330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380315.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	ENST00000380315.2	TSL:5	c.-47C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000369671.2	F8W6P5
	HBB	ENST00000380315.2	TSL:5	c.-47C>T		5_prime_UTR	Exon 2 of 4	ENSP00000369671.2	F8W6P5
	ENSG00000298932	ENST00000759072.1		n.265+1812G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.957 AC: 145258 AN: 151794 Hom.: 70043 Cov.: 29

Gnomad AFR AF: 0.974

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.993

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.890

Gnomad FIN AF: 0.972

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.951

GnomAD4 exome AF: 0.908 AC: 12555 AN: 13832 Hom.: 5828 Cov.: 0 AF XY: 0.905 AC XY: 6602 AN XY: 7292

African (AFR) AF: 0.968 AC: 151 AN: 156

American (AMR) AF: 0.814 AC: 2340 AN: 2874

Ashkenazi Jewish (ASJ) AF: 0.987 AC: 154 AN: 156

East Asian (EAS) AF: 0.562 AC: 615 AN: 1094

South Asian (SAS) AF: 0.898 AC: 1668 AN: 1858

European-Finnish (FIN) AF: 0.934 AC: 211 AN: 226

Middle Eastern (MID) AF: 1.00 AC: 18 AN: 18

European-Non Finnish (NFE) AF: 0.997 AC: 6875 AN: 6898

Other (OTH) AF: 0.947 AC: 523 AN: 552

GnomAD4 genome AF: 0.957 AC: 145364 AN: 151910 Hom.: 70092 Cov.: 29 AF XY: 0.950 AC XY: 70562 AN XY: 74242

African (AFR) AF: 0.975 AC: 40379 AN: 41434

American (AMR) AF: 0.845 AC: 12881 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 3444 AN: 3470

East Asian (EAS) AF: 0.621 AC: 3194 AN: 5140

South Asian (SAS) AF: 0.890 AC: 4280 AN: 4808

European-Finnish (FIN) AF: 0.972 AC: 10201 AN: 10492

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67785 AN: 68010

Other (OTH) AF: 0.948 AC: 1997 AN: 2106

Alfa AF: 0.961 Hom.: 32911

Bravo AF: 0.947

Asia WGS AF: 0.761 AC: 2647 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	beta Thalassemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.062
DANN	Benign	0.60
PhyloP100		-2.0
PromoterAI		0.0066	Neutral

Splicing

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

Other links and lift over

dbSNP: rs10742584; hg19: chr11-5248770;