rs41321052

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1PM2PP3_StrongBP6

The NM_000517.6(HBA2):c.307A>C(p.Ser103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.811

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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000517.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

BP6

Variant 16-173478-A-C is Benign according to our data. Variant chr16-173478-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1330535.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.307A>C	p.Ser103Arg	missense_variant	Exon 3 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.307A>C	p.Ser103Arg	missense_variant	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000806

AC:

AN:

248256

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31322

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111896

Other (OTH)

AF:

0.00

AC:

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 01, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.0000081 (2/248256 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In vitro studies have shown that Hb Manitoba I is mildly unstable and has reduced dissociation (PMID: 7803274 (1994), 5452728 (1970)). Individuals heterozygous for this variant have a normal clinical presentation, with Hb Manitoba I accounting for 19% of total hemoglobin (PMID: 11791879 (2001), 7803274 (1994), 6547932 (1984), 5452728 (1970)). 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Feb 09, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.17

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

-0.093

PhyloP100

-0.81

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.023

D;D

Vest4

0.76

MutPred

0.96

Gain of catalytic residue at S103 (P = 0.0654);.;

MVP

1.0

MPC

1.7

ClinPred

0.82

GERP RS

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.94

Mutation Taster

=6/94

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over