16-172957-G-C

Variant names:

• chr16-172957-G-C
• rs63750367
• NM_000517.6:c.45G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM5 PP3_Strong BP6

The NM_000517.6(HBA2):​c.45G>C​(p.Trp15Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W15R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 1)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.88
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-172955-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3063969.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• BP6: Variant 16-172957-G-C is Benign according to our data. Variant chr16-172957-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 439121.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.45G>C	p.Trp15Cys	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.45G>C	p.Trp15Cys	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 1

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Apr 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heterozygosity for this variant is associated with a normal clinical presentation. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant.

Oct 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Bladensburg variant (HBA2: c.45G>C; p.Trp15Cys, also known as Trp14Cys when numbered from the mature protein, rs63750367, HbVar ID: 2587) is reported in the literature in a healthy individual (HbVar database and references therein). This variant is reported in ClinVar (Variation ID: 439121) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.69). Based on available information, this variant is considered to be likely benign. References: Link to HbVar link: https://globin.bx.psu.edu/hbvar/hbvar.html

alpha Thalassemia Uncertain:1

May 20, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	23
DANN	Benign	0.97
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		3.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0060	D
Vest4		0.56
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		0.066	Neutral
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750367; hg19: chr16-222956;