rs281864844

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G58R) has been classified as Likely benign.

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.72

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

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 id is 801171.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.173G>A	p.Gly58Asp	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 link	c.173G>A	p.Gly58Asp	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1 link	c.140G>A	p.Gly47Asp	missense_variant	Exon 2 of 2	1		ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1 link	n.309G>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1 link	c.77G>A	p.Gly26Asp	missense_variant	Exon 2 of 3	2		ENSP00000380908.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

116406

Hom.:

Cov.:

FAILED QC

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:

AN:

983530

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

500950

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000139

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

116406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

55732

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign: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

BayesDel_addAF

Uncertain

0.14

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

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Benign

-0.60

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.053

T;D

Vest4

0.50

MutPred

0.48

Loss of ubiquitination at K57 (P = 0.0795);.;

MVP

1.0

MPC

1.6

ClinPred

0.74

GERP RS

-8.3

gMVP

0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over