rs558457816

Positions:

• chr16-173034-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000517.6(HBA2):​c.95+27C>T variant causes a intron 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (0 hom., cov: 4)
  • Exomes 𝑓: 0.0081 (64 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.782

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=-0.91).
• BP6: Variant 16-173034-C-T is Benign according to our data. Variant chr16-173034-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 439773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00812 (3751/461772) while in subpopulation NFE AF= 0.0105 (2867/273496). AF 95% confidence interval is 0.0102. There are 64 homozygotes in gnomad4_exome. There are 1857 alleles in male gnomad4_exome subpopulation. Median coverage is 2. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 64 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.95+27C>T		intron_variant		ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.95+27C>T		intron_variant		1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000484216.1	c.64+27C>T		intron_variant		1		ENSP00000495899
HBA2	ENST00000482565.1	n.141C>T		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-2+76C>T		intron_variant		2		ENSP00000380908

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 86 AN: 18128 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.0139

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00398

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00213

Gnomad FIN AF: 0.00200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00705

Gnomad OTH AF: 0.00327

GnomAD3 exomes AF: 0.00696 AC: 427 AN: 61338 Hom.: 8 AF XY: 0.00673 AC XY: 210 AN XY: 31216

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00774

Gnomad ASJ exome AF: 0.00469

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00238

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00812 AC: 3751 AN: 461772 Hom.: 64 Cov.: 2 AF XY: 0.00761 AC XY: 1857 AN XY: 243904

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00678

Gnomad4 ASJ exome AF: 0.00845

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00207

Gnomad4 FIN exome AF: 0.00652

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00470 AC: 85 AN: 18098 Hom.: 0 Cov.: 4 AF XY: 0.00535 AC XY: 43 AN XY: 8040

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00522

Gnomad4 ASJ AF: 0.00398

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00216

Gnomad4 FIN AF: 0.00200

Gnomad4 NFE AF: 0.00695

Gnomad4 OTH AF: 0.00318

Alfa AF: 0.00583 Hom.: 3

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 21, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.9
DANN	Benign	0.84

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: rs558457816; hg19: chr16-223033;