16-173540-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000517.6(HBA2):c.369C>G(p.His123Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,607,450 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.000074 ( 0 hom., cov: 25)

Exomes 𝑓: 0.00013 ( 3 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: -1.38

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_000517.6

BP4

Computational evidence support a benign effect (MetaRNN=0.19518125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.369C>G	p.His123Gln	missense_variant	3/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.369C>G	p.His123Gln	missense_variant	3/3	1	NM_000517.6	P1
HBA2	ENST00000482565.1 linkuse as main transcript	n.505C>G		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1 linkuse as main transcript	n.121G>C		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1 linkuse as main transcript	c.273C>G	p.His91Gln	missense_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000740

AC:

AN:

148608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000157

AC:

AN:

248160

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

134542

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1458726

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

725446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000740

AC:

AN:

148724

Hom.:

Cov.:

AF XY:

0.0000964

AC XY:

AN XY:

72636

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00136

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000939

AC:

AN:

3208

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 29, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 27, 2023	The Hb Westmead variant (HBA2: c.369C>G; p.His123Gln, also known as His122Gln when numbered from the mature protein, rs41479347, HbVar ID: 185) has been reported in the heterozygous state in multiple individuals of East Asian descent, but has not been associated with significant clinical symptoms (Jiang 2020, Ma 2001, Viprakasit 2014, Wong 2004, HbVar database and references therein). This variant has been reported in homozygous individuals with mild anemia (Jiang 2020). However, it is an unstable hemoglobin variant, and its co-occurrence with beta thalassemia results in milder symptoms for the patient (Scheps 2020, Wong 2004, HbVar database and references therein). This variant is reported in ClinVar (Variation ID: 439771). It is found in the East Asian population with an overall allele frequency of 0.17% (33/19844 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.618). However, given the lack of clinical and functional data, the significance of the p.His123Gln variant is uncertain at this time. References: HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Jiang F et al. Hb Westmead (HBA2: c.369C>G): Hematological Characteristics in Heterozygotes with and without a0-Thalassemia. Hemoglobin. 2020 May;44(3):153-155. PMID: 32436451. Ma E et al. Interaction between (--SEA) alpha-thalassemia deletion and uncommon non-deletional alpha-globin gene mutations in Chinese patients. Haematologica. 2001; 86(5):539-40. PMID: 11410420. Scheps KG et al. Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis. Hum Mutat. 2020 Jan;41(1):81-102. PMID: 31553106. Viprakasit V et al. Clinical presentation and molecular identification of four uncommon alpha globin variants in Thailand. Acta Haematol. 2014;131(2):88-94. PMID: 24081251. Wong W et al. Thalassemia intermedia due to co-inheritance of beta0/beta(+)-thalassemia and (--SEA) alpha-thalassemia/Hb Westmead (alpha122(H5)His > Gln (alpha2)) in a Chinese family. Hemoglobin. 2004; 28(2):151-6. PMID: 15182058. -

Heinz body anemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2022

- -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 28, 2022

- -

Erythrocytosis, familial, 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2022

- -

Hemoglobin H disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2022

- -

HEMOGLOBIN WESTMEAD

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Pathogenic

0.31

Cadd

Benign

8.0

Dann

Benign

0.97

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.20

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

0.47

MutationTaster

Benign

0.95

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.18

T;T

Vest4

0.41

MutPred

0.88

Gain of ubiquitination at K128 (P = 0.1103);.;

MVP

1.0

MPC

2.4

ClinPred

0.29

GERP RS

-8.5

gMVP

0.85

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

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