rs41322148

Variant names:

• chr11-5254939-G-A
• rs7482144
• ENST00000380259.7:n.*1093C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000380259.7(ENSG00000239920):​n.*1093C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 560,744 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.21 (15 hom., cov: 29)
  • Exomes 𝑓: 0.22 (1 hom.)
• Consequence: ENSG00000239920 ENST00000380259.7 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.541
• Publications: 141 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-5254939-G-A is Benign according to our data. Variant chr11-5254939-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14984.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.-211C>T		upstream_gene_variant		ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000239920	ENST00000380259.7	n.*1093C>T		non_coding_transcript_exon_variant	Exon 7 of 8	5		ENSP00000369609.3
ENSG00000239920	ENST00000380259.7	n.*1093C>T		3_prime_UTR_variant	Exon 7 of 8	5		ENSP00000369609.3
HBG2	ENST00000336906.6	c.-211C>T		upstream_gene_variant		1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.-211C>T		upstream_gene_variant				ENSP00000495346.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31089 AN: 150068 Hom.: 15 Cov.: 29

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.218 AC: 89641 AN: 410562 Hom.: 1 Cov.: 0 AF XY: 0.219 AC XY: 47503 AN XY: 216468

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.124 AC: 1459 AN: 11788

American (AMR) AF: 0.161 AC: 2841 AN: 17642

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 1989 AN: 12698

East Asian (EAS) AF: 0.117 AC: 3414 AN: 29254

South Asian (SAS) AF: 0.214 AC: 8896 AN: 41554

European-Finnish (FIN) AF: 0.191 AC: 5101 AN: 26704

Middle Eastern (MID) AF: 0.159 AC: 289 AN: 1822

European-Non Finnish (NFE) AF: 0.248 AC: 60691 AN: 245176

Other (OTH) AF: 0.207 AC: 4961 AN: 23924

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.207 AC: 31096 AN: 150182 Hom.: 15 Cov.: 29 AF XY: 0.203 AC XY: 14930 AN XY: 73372

African (AFR) AF: 0.143 AC: 5864 AN: 41054

American (AMR) AF: 0.181 AC: 2724 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 595 AN: 3422

East Asian (EAS) AF: 0.110 AC: 566 AN: 5148

South Asian (SAS) AF: 0.229 AC: 1082 AN: 4730

European-Finnish (FIN) AF: 0.188 AC: 1957 AN: 10430

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17636 AN: 67048

Other (OTH) AF: 0.211 AC: 435 AN: 2064

Alfa AF: 0.263 Hom.: 1771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBG2 c.-211C>T variant (rs7482144, rs1060499525, HbVar ID: 3260), also known as -158C>T and XmnI, is a common variant in the 5' untranslated region. While not associated with hereditary persistence of fetal hemoglobin (HPFH) in healthy adults, this variant has been described as a modifier of beta-thalassemia (Ma 2007, Nguyen 2010) and beta-globin variants such as Hb S (Akinbami 2016) due to its association with increased levels of HbF. This variant is also reported in ClinVar (Variation ID: 14984) and is found in the general population with an overall allele frequency of 20.7% (at least 6412/30916 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Akinbami AO et al. Hereditary Persistence of Fetal Hemoglobin Caused by Single Nucleotide Promoter Mutations in Sickle Cell Trait and Hb SC Disease. Hemoglobin. 2016;40(1):64-5. PMID: 26372199. Ma Q et al. Beta-globin gene cluster polymorphisms are strongly associated with severity of HbE/beta(0)-thalassemia. Clin Genet. 2007 Dec;72(6):497-505. PMID: 17894837. Nguyen TK et al. The XmnI (G)gamma polymorphism influences hemoglobin F synthesis contrary to BCL11A and HBS1L-MYB SNPs in a cohort of 57 beta-thalassemia intermedia patients. Blood Cells Mol Dis. 2010 Aug 15;45(2):124-7. PMID: 20472475. -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary persistence of fetal hemoglobin Uncertain:1

Dec 01, 2010

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.75
PhyloP100		0.54
PromoterAI		0.073	Neutral
Mutation Taster		=296/4	polymorphism

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: rs7482144; hg19: chr11-5276169;