rs3759071

chr11-5270302-G-Achr11-5270302-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000292896.3(HBE1):c.-266-146C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 167,790 control chromosomes in the GnomAD database, including 19,120 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 0.47 (17217 hom., cov: 32)
  • Exomes 𝑓: 0.46 (1903 hom.)
• Consequence: HBE1 ENST00000292896.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.913

Genes affected

HBE1 (HGNC:4830): (hemoglobin subunit epsilon 1) The epsilon globin gene (HBE) is normally expressed in the embryonic yolk sac: two epsilon chains together with two zeta chains (an alpha-like globin) constitute the embryonic hemoglobin Hb Gower I; two epsilon chains together with two alpha chains form the embryonic Hb Gower II. Both of these embryonic hemoglobins are normally supplanted by fetal, and later, adult hemoglobin. The five beta-like globin genes are found within a 45 kb cluster on chromosome 11 in the following order: 5'-epsilon - G-gamma - A-gamma - delta - beta-3' [provided by RefSeq, Jul 2008]

HBG2 (HGNC:4832): (hemoglobin subunit gamma 2) The gamma globin genes (HBG1 and HBG2) are normally expressed in the fetal liver, spleen and bone marrow. Two gamma chains together with two alpha chains constitute fetal hemoglobin (HbF) which is normally replaced by adult hemoglobin (HbA) at birth. In some beta-thalassemias and related conditions, gamma chain production continues into adulthood. The two types of gamma chains differ at residue 136 where glycine is found in the G-gamma product (HBG2) and alanine is found in the A-gamma product (HBG1). The former is predominant at birth. 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBE1	ENST00000292896.3	c.-266-146C>T		intron_variant		1		P1
HBE1	ENST00000380237.5	c.-266-146C>T		intron_variant		1		P1
HBG2	ENST00000380252.6	c.-73-15788C>T		intron_variant		3
	ENST00000646569.1	n.59-10765C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70727 AN: 151866 Hom.: 17202 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.507

GnomAD4 exome AF: 0.465 AC: 7349 AN: 15806 Hom.: 1903 AF XY: 0.473 AC XY: 3800 AN XY: 8030

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.578

Gnomad4 ASJ exome AF: 0.588

Gnomad4 EAS exome AF: 0.727

Gnomad4 SAS exome AF: 0.567

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.460

GnomAD4 genome AF: 0.466 AC: 70789 AN: 151984 Hom.: 17217 Cov.: 32 AF XY: 0.471 AC XY: 35003 AN XY: 74260

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.595

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.583

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.509

Alfa AF: 0.477 Hom.: 17829

Bravo AF: 0.473

Asia WGS AF: 0.624 AC: 2170 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	6.0
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3759071; hg19: chr11-5291532;