chr16-173175-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000517.6(HBA2):c.146T>G(p.Leu49Arg) 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000010 ( 0 hom., cov: 12)

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:2

Conservation

PhyloP100: 2.43

Publications

1 publications found

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 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

HBA2 links:

ENSG00000294455 (HGNC:):

ENSG00000294455 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_000517.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.146T>G	p.Leu49Arg	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.146T>G	p.Leu49Arg	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

AF:

0.00000998

AC:

AN:

100234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000561

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

Cov.:

GnomAD4 genome

AF:

0.00000998

AC:

AN:

100234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

47508

show subpopulations

African (AFR)

AF:

0.0000561

AC:

AN:

17836

American (AMR)

AF:

0.00

AC:

AN:

10356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2812

East Asian (EAS)

AF:

0.00

AC:

AN:

3690

South Asian (SAS)

AF:

0.00

AC:

AN:

2296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53688

Other (OTH)

AF:

0.00

AC:

AN:

1256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

May 16, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA2 c.146T>G (p.Leu49Arg) variant has been reported in the published literature with normal stability and heterozygote carriers present with normal clinical presentations (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter) and PMIDs: 7096113 (1982), 3384700 (1988), 7803274 (1994)). While the variant has been detected in healthy individuals along with Hemoglobin S or Hemoglobin C, the phenotype of this variant in the presence of other alpha variants is not well known (PMIDs: 1115799 (1975), 7295286 (1981), and 7096113 (1982)). The frequency of this variant in the general population, 0.00001 (1/100234 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jun 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb Montgomery variant (HBA2: c.146T>G; p.Leu49Arg, also known as Leu48Arg when numbered from the mature protein, rs41392146, HbVar ID: 69), is reported in the literature in individuals with no associated clinical symptoms, and is considered a stable hemoglobin variant (Molchanova 1994, HbVar and references therein). However, the phenotype of this variant in the presence of other alpha globin variants is unknown. This variant is reported in ClinVar (Variation ID: 15637), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 49 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.754). Due to limited information, the clinical significance of the Hb Montgomery variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Molchanova T et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 88(2):300-6. PMID: 7803274. -

not specified

Uncertain:1

May 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HBA2 c.146T>G (p.Leu49Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.146T>G has been reported in the literature as a stable hemoglobin variant in asymptomatic individuals (e.g. Brimhall_1975, Molchanova_1994). These reports do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 7803274, 1115799). ClinVar contains an entry for this variant (Variation ID: 15637). Based on the evidence outlined above, the variant was classified as uncertain significance. -

alpha Thalassemia

Uncertain:1

Nov 01, 2018

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

HEMOGLOBIN MONTGOMERY

Other:1

Sep 05, 2023

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN BIRMINGHAM (USA)

Other:1

Sep 05, 2023

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.93

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

0.98

PhyloP100

2.4

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0040

D;D

Vest4

0.44

MutPred

0.90

Gain of solvent accessibility (P = 0.0156);.;

MVP

1.0

MPC

2.3

ClinPred

0.98

GERP RS

4.2

PromoterAI

0.0060

Neutral

(source)

gMVP

0.94

Mutation Taster

=21/79

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over