rs281864821

Variant names:

• chr16-172985-T-G
• rs281864821
• NM_000517.6:c.73T>G

Your query was ambiguous. Multiple possible variants found:

• chr16-172985-T-G
• chr16-172985-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP3_Moderate PP5_Moderate

The NM_000517.6(HBA2):​c.73T>G​(p.Tyr25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y25C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 2)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.489
• Publications: 1 publications found

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]

HBA2 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Heinz body anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• unstable hemoglobin disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 12 uncertain in NM_000517.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 16-172985-T-G is Pathogenic according to our data. Variant chr16-172985-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2413187.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. 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
	HBA2	NM_000517.6	MANE Select	c.73T>G	p.Tyr25Asp	missense	Exon 1 of 3	NP_000508.1	D1MGQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.73T>G	p.Tyr25Asp	missense	Exon 1 of 3	ENSP00000251595.6	P69905
	HBA2	ENST00000484216.1	TSL:1	c.40T>G	p.Tyr14Asp	missense	Exon 1 of 2	ENSP00000495899.1	A0A2R8Y7C0
	HBA2	ENST00000482565.1	TSL:1	n.92T>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 421084 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 221238

African (AFR) AF: 0.00 AC: 0 AN: 10312

American (AMR) AF: 0.00 AC: 0 AN: 18346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13014

East Asian (EAS) AF: 0.00 AC: 0 AN: 28882

South Asian (SAS) AF: 0.00 AC: 0 AN: 44468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1802

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 252514

Other (OTH) AF: 0.00 AC: 0 AN: 24142

GnomAD4 genome Cov.: 2

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	alpha Thalassemia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.049	N
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.22	D
PhyloP100		0.49
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.023	D
Vest4		0.43
MutPred		0.74		Gain of disorder (P = 0.0291)
MVP		0.98
MPC		3.2
ClinPred		0.93	D
GERP RS		2.8
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.97
Mutation Taster		=35/65	disease causing

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: rs281864821; hg19: chr16-222984;