16-172985-T-G

Variant names:

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

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, 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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.73T>G	p.Tyr25Asp	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.73T>G	p.Tyr25Asp	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

alpha Thalassemia Pathogenic:1

Feb 02, 2023

Department of Medical Genomics, Royal Prince Alfred Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This missense variant is detected in an adult patient with normal haemoglobin level, but with microcytic, hypochromic red blood cells (MCV 75 ref. 80-100; MCH 24.5 ref 27-32). Haemoglobin electrophoresis and iron studies were normal. Normal bilirubin level. No deletion was detected in the haemoglobin alpha locus, and no mutation was detected in the haemoglobin beta gene. The variant is reported on the HbVar database as Hb Creve Coeur, and is reported to be mildly stable with normal oxygen affinity. A different missense variant, p.(Tyr25His), known as Hb Luxembourg, is reported as a mildly unstable variant haemoglobin (PMID: 2599879, 1917540). -

not provided Pathogenic:1

Mar 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA2 c. 73T>G; p. Tyr25Asp variant (Hb Creve Coeur, rs281864821, HbVar ID: 2501) is a mildly unstable hemoglobin documented in an individual affected with mild microcytotic anemia (see HbVar and references therein). Additionally, the other variant at this codon (c.73T>C; p. Tyr25His, also known as Hb Luxembourg) has been found in association with mild hemolytic anemia, bilirubinemia, reticulocytosis, mild Hb instability and abnormal electrophoresis, hence are considered pathogenic (Groff 1989, Moo-Penn 1991). This variant is also reported in ClinVar (Variation ID: 2413187) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid substitution involves the tyrosine residue at a structurally critical position as part of the alpha1beta 1 contacting interphase (Groff 1989). The tyrosine at codon 25 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.542). Based on available information, the p. Tyr25Asp variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Groff P, et al. HB Luxembourg [alpha24(B5) Tyr?His]: A New Unstable Variant. Hemoglobin. 1989;13(5):429-36. PMID: 2599879. Moo-Penn WF et al. Hb Luxembourg [alpha 24(B5)Tyr----His], Hb Maputo [beta 47(CD6)Asp----Tyr], and Hb Fukuyama [beta 77(EF1)His----Tyr]. Hemoglobin. 1991;15(1-2):97-101. PMID: 1917540. -

Computational scores

Source: dbNSFP v4.3

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;