Variant 16-173175-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_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

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.146T>G	p.Leu49Arg	missense_variant	2/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.146T>G	p.Leu49Arg	missense_variant	2/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000484216.1 linkuse as main transcript	c.116T>G	p.Leu39Arg	missense_variant	2/2	1		ENSP00000495899
HBA2	ENST00000482565.1 linkuse as main transcript	n.282T>G		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.50T>G	p.Leu17Arg	missense_variant	2/3	2		ENSP00000380908

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

Gnomad4 AFR

AF:

0.0000561

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: Uncertain significance

Submissions summary: Uncertain:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 12, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 17, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 01, 2018

- -

HEMOGLOBIN MONTGOMERY

Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 05, 2023

- -

HEMOGLOBIN BIRMINGHAM (USA)

Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

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

MutationTaster

Benign

0.85

D;D

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

gMVP

0.94

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