11-5255848-A-T

Variant names:

• chr11-5255848-A-T
• rs2855123
• ENST00000380259.7:n.*867-683T>A

Variant summary

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

The ENST00000380259.7(ENSG00000239920):​n.*867-683T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 151,992 control chromosomes in the GnomAD database, including 15,701 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 0.43 (15701 hom., cov: 33)
• Consequence: ENSG00000239920 ENST00000380259.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.532
• Publications: 4 publications found

Genes affected

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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

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
ENSG00000239920	ENST00000380259.7	n.*867-683T>A		intron_variant	Intron 6 of 7	5		ENSP00000369609.3
HBG2	ENST00000380252.6	c.-73-1334T>A		intron_variant	Intron 1 of 2	3		ENSP00000369602.2
ENSG00000239920	ENST00000643199.1	n.1053-683T>A		intron_variant	Intron 6 of 6
ENSG00000239920	ENST00000646569.1	n.280-683T>A		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65863 AN: 151874 Hom.: 15690 Cov.: 33

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.491

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

GnomAD4 genome AF: 0.434 AC: 65917 AN: 151992 Hom.: 15701 Cov.: 33 AF XY: 0.440 AC XY: 32679 AN XY: 74292

African (AFR) AF: 0.247 AC: 10254 AN: 41466

American (AMR) AF: 0.577 AC: 8806 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2154 AN: 3468

East Asian (EAS) AF: 0.775 AC: 4006 AN: 5172

South Asian (SAS) AF: 0.545 AC: 2625 AN: 4814

European-Finnish (FIN) AF: 0.461 AC: 4855 AN: 10534

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31524 AN: 67954

Other (OTH) AF: 0.493 AC: 1042 AN: 2112

Alfa AF: 0.435 Hom.: 1862

Bravo AF: 0.431

Asia WGS AF: 0.596 AC: 2073 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.83
PhyloP100		0.53
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: rs2855123; hg19: chr11-5277078;