rs772829778

Positions:

• chr16-172889-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000517.6(HBA2):​c.-24C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.082 (1242 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.42

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-172889-C-G is Benign according to our data. Variant chr16-172889-C-G is described in ClinVar as [Benign]. Clinvar id is 439113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.-24C>G		5_prime_UTR_variant	1/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.-24C>G		5_prime_UTR_variant	1/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000482565.1			upstream_gene_variant		1
HBA2	ENST00000397806.1			upstream_gene_variant		2		ENSP00000380908

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 12 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AMR AF: 0.00

Gnomad NFE AF: 0.00

GnomAD3 exomes AF: 0.0687 AC: 3594 AN: 52298 Hom.: 234 AF XY: 0.0707 AC XY: 1868 AN XY: 26412

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0618

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.000387

Gnomad SAS exome AF: 0.0898

Gnomad FIN exome AF: 0.0696

Gnomad NFE exome AF: 0.0968

Gnomad OTH exome AF: 0.0995

GnomAD4 exome AF: 0.0816 AC: 17551 AN: 215140 Hom.: 1242 Cov.: 0 AF XY: 0.0851 AC XY: 9799 AN XY: 115192

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.0578

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.000407

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.0513

Gnomad4 NFE exome AF: 0.0866

Gnomad4 OTH exome AF: 0.0794

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0351 Hom.: 11

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 31478238) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 05, 2023	- -

alpha Thalassemia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.59
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs772829778; hg19: chr16-222888;