rs7482144

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380259.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG2	NM_000184.3	MANE Select	c.-211C>T		upstream_gene	N/A	NP_000175.1	D9YZU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000239920	ENST00000380259.7	TSL:5	n.*1093C>T		non_coding_transcript_exon	Exon 7 of 8	ENSP00000369609.3	A0A2U3TZJ3
	ENSG00000239920	ENST00000380259.7	TSL:5	n.*1093C>T		3_prime_UTR	Exon 7 of 8	ENSP00000369609.3	A0A2U3TZJ3
	HBG2	ENST00000380252.6	TSL:3	c.-73-425C>T		intron	N/A	ENSP00000369602.2	E9PBW4

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), 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Hereditary persistence of fetal hemoglobin (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;