rs7482144

Positions:

• chr11-5254939-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000380252.6(HBG2):​c.-73-425C>T variant causes a intron 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: HBG2 ENST00000380252.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.541

Genes affected

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 -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 id is 14984.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• 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/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000380252.6	c.-73-425C>T		intron_variant		3		ENSP00000369602
	ENST00000646569.1	n.506C>T		non_coding_transcript_exon_variant	5/5

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

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.207

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

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.211

Alfa AF: 0.260 Hom.: 813

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Hereditary persistence of fetal hemoglobin Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Dec 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs7482144; hg19: chr11-5276169;