rs281864844

Variant names:

• chr16-173202-G-A
• rs281864844
• NM_000517.6:c.173G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP6

The NM_000517.6(HBA2):​c.173G>A​(p.Gly58Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 17)
  • Exomes 𝑓: 0.0000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.72
• 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 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 11 uncertain in NM_000517.6
• BP6: Variant 16-173202-G-A is Benign according to our data. Variant chr16-173202-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 801171.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.173G>A	p.Gly58Asp	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.173G>A	p.Gly58Asp	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 116406 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000102 AC: 1 AN: 983530 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 500950

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19580

American (AMR) AF: 0.00 AC: 0 AN: 35718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22516

East Asian (EAS) AF: 0.00 AC: 0 AN: 34128

South Asian (SAS) AF: 0.00 AC: 0 AN: 70322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3198

European-Non Finnish (NFE) AF: 0.00000139 AC: 1 AN: 719836

Other (OTH) AF: 0.00 AC: 0 AN: 44036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 116406 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 55732

African (AFR) AF: 0.00 AC: 0 AN: 22546

American (AMR) AF: 0.00 AC: 0 AN: 12156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3070

East Asian (EAS) AF: 0.00 AC: 0 AN: 4140

South Asian (SAS) AF: 0.00 AC: 0 AN: 2984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60176

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Oct 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb J-Norfolk variant (HBA2: c.173G>A; p.Gly58Asp, also known as Gly57Asp when numbered from the mature protein, and also known as Hb Kagoshima, Hb Nishik-I, Hb Nishik-II, Hb Nishik-III, rs281864844, HbVar ID:84, ClinVar Variation ID: 801171) is reported in the literature in multiple asymptomatic individuals in the heterozygous state (see HbVar link, Imamura 1966, Mehrotra 1975, Nair 2018). However, the phenotype of this variant in the presence of other alpha globin variants is unknown. This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.571). Based on available information, this variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Imamura T. Hemoglobin Kagoshima: an example of hemoglobin Norfolk in a Japanese family. Am J Hum Genet. 1966 Nov;18(6):584-93. PMID: 5927878. Mehrotra TN et al. Haemoglobin norfolk in nepali gorkhas. Humangenetik. 1975;27(4):347-9. PMID: 1150256. Nair SB et al. Hematological and Molecular Findings in the First Case of Hb J-Norfolk (HBA2: c.173G>A (or HBA1)) in an Indian Patient. Hemoglobin. 2018 Sep-Nov;42(5-6):333-335. PMID: 30646764.

Nov 04, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	0.64
DANN	Benign	0.92
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.60	T
PhyloP100		-1.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.053	T
Vest4		0.50
MutPred		0.48		Loss of ubiquitination at K57 (P = 0.0795)
MVP		1.0
MPC		1.6
ClinPred		0.74	D
GERP RS		-8.3
PromoterAI		0.013	Neutral
gMVP		0.85
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs281864844; hg19: chr16-223201;