11-5289833-A-T

Variant names:

• chr11-5289833-A-T
• rs11036644
• ENST00000292896.3:c.-266-19677T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000292896.3(HBE1):​c.-266-19677T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 152,156 control chromosomes in the GnomAD database, including 14,255 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 0.40 (14255 hom., cov: 33)
• Consequence: HBE1 ENST00000292896.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.655
• Publications: 4 publications found

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]

ENSG00000239920 (HGNC:):

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]

HBG2 Gene-Disease associations (from GenCC):

• hemoglobinopathy Toms River

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• cyanosis, transient neonatal

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000292896.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBE1	ENST00000292896.3	TSL:1	c.-266-19677T>A		intron	N/A	ENSP00000292896.2
	HBE1	ENST00000380237.5	TSL:1	c.-309-7882T>A		intron	N/A	ENSP00000369586.1
	ENSG00000239920	ENST00000380259.7	TSL:5	n.*867-34668T>A		intron	N/A	ENSP00000369609.3

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61166 AN: 152040 Hom.: 14246 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.456

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

GnomAD4 genome AF: 0.402 AC: 61190 AN: 152156 Hom.: 14255 Cov.: 33 AF XY: 0.413 AC XY: 30745 AN XY: 74392

African (AFR) AF: 0.173 AC: 7187 AN: 41520

American (AMR) AF: 0.570 AC: 8710 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1807 AN: 3470

East Asian (EAS) AF: 0.719 AC: 3724 AN: 5178

South Asian (SAS) AF: 0.547 AC: 2638 AN: 4826

European-Finnish (FIN) AF: 0.507 AC: 5367 AN: 10576

Middle Eastern (MID) AF: 0.566 AC: 164 AN: 290

European-Non Finnish (NFE) AF: 0.444 AC: 30199 AN: 67994

Other (OTH) AF: 0.459 AC: 968 AN: 2110

Alfa AF: 0.263 Hom.: 663

Bravo AF: 0.394

Asia WGS AF: 0.572 AC: 1988 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.54
DANN	Benign	0.47
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11036644; hg19: chr11-5311063;