rs41407250

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_StrongBP6

The NM_000558.5(HBA1):c.49A>G(p.Lys17Glu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. 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. K17M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:5

Conservation

PhyloP100: 4.90

Publications

6 publications found

Variant links:

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) 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]

HBA1 Gene-Disease associations (from GenCC):

alpha thalassemia spectrum
Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
erythrocytosis, familial, 7
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
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
methemoglobinemia, alpha type
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Heinz body anemia
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HBA1 links:

ENSG00000294436 (HGNC:):

ENSG00000294436 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

BP6

Variant 16-176765-A-G is Benign according to our data. Variant chr16-176765-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15746.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.49A>G	p.Lys17Glu	missense_variant	Exon 1 of 3	ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9 link	c.49A>G	p.Lys17Glu	missense_variant	Exon 1 of 3	1	NM_000558.5	ENSP00000322421.5		P69905

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150228

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00000599

AC:

AN:

166854

AF XY:

0.0000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000382

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000417

AC:

AN:

1437400

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

713834

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32482

American (AMR)

AF:

0.0000238

AC:

AN:

42026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25758

East Asian (EAS)

AF:

0.00

AC:

AN:

38696

South Asian (SAS)

AF:

0.00

AC:

AN:

83126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4430

European-Non Finnish (NFE)

AF:

0.00000454

AC:

AN:

1100134

Other (OTH)

AF:

0.00

AC:

AN:

59352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000244285), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

150228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73186

African (AFR)

AF:

0.00

AC:

AN:

41152

American (AMR)

AF:

0.00

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.00

AC:

AN:

5094

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66820

Other (OTH)

AF:

0.00

AC:

AN:

2056

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb I variant (HBA1 or HBA2: c.49A>G; p.Lys17Glu, also known as Lys16Glu when numbered from the mature protein, rs41407250, HbVar ID: 19) has been reported in the literature as a stable hemoglobin variant present in normal heterozygous individuals (Arya 2009, Lin 2013, Molchanova 1994, HbVar database and references therein) and in an individual without clinical symptoms who also carried an alpha globin deletion (Liebhaber 1984). The variant is listed in ClinVar (Variation ID: 15746) and is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict the variant is deleterious (REVEL: 0.732). At least one report suggests this variant may interfere with measurements of Hb A1c in diabetic individuals (Arya 2009). Considering available information, the Hb I variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Arya V et al. Rare hemoglobin variant Hb I Philadelphia in North Indian family. Ann Hematol. 2009;88(9):927-929. PMID: 19234704. Liebhaber S et al. Hemoglobin I mutation encoded at both alpha-globin loci on the same chromosome: concerted evolution in the human genome. Science. 1984; 226(4681):1449-51. PMID: 6505702. Lin M et al. Molecular epidemiological survey of hemoglobinopathies in the Wuxi region of Jiangsu Province, eastern China. Hemoglobin. 2013;37(5):454-466. PMID: 23806067. Molchanova TP et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994;88(2):300-306. PMID: 7803274. -

Jan 30, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA1 c.49A>G (p.Lys17Glu) variant has been reported in the published literature to have normal stability, with oxygen equilibrium and kinetic properties similar to wild type Hb A (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter), PMID: 4444049 (1974)). Individuals who are heterozygous for this variant have a normal clinical presentation (PMIDs: 23806067 (2013), 6085353 (1984), 740406 (1978)). Co-occurrence of this variant with a beta-thalassemia pathogenic variant presented with mild hypochromic microcytic anemia (PMID: 19234704 (2009)). The frequency of this variant in the general population, 0.000006 (1/166854 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Benign:1

Aug 04, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HBA1 c.49A>G (p.Lys17Glu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-06 in 166854 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.49A>G variant (aka Hemoglobin I, Hb I Burlington), is a known hemoglobin variant with altered electrophoretic mobility, and was reported in several asymptomatic heterozygotes, who had no hematological abnormalities (e.g. Saito_1984, Fleming_1978, Arya_2009, Lin_2013). To our knowledge, no homozygous occurrences, or compound heterozygotes with pathogenic HBA1 (or HBA2) variants were reported. The variant was reported in combination with a pathogenic HBB variant, however this individual was only mildly anemic, with a mild hypochromia and microcytosis, which are consistent with the beta-thalassemia carrier state (Arya_2009). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the oxygen equilibrium and kinetic properties of hemoglobin I were indistinguishable from those of the WT (McDonald_1974). Studies also reported that the variant might (slightly) interfere with the measurement of glycosylated hemoglobin (HbA1c) that laboratories should be aware of to avoid mismanagement of individuals carrying this variant (Arya_2009, Zechmeister_2022). The following publications have been ascertained in the context of this evaluation (PMID: 4444049, 6085353, 740406, 19234704, 23806067, 35378091, 5480848). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

HBA1-related disorder

Benign:1

Sep 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

HEMOGLOBIN I (TEXAS)

Other:1

May 10, 2018

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN I (SKAMANIA)

Other:1

May 10, 2018

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN I (BURLINGTON)

Other:1

May 10, 2018

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN I

Other:1

May 10, 2018

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN I (PHILADELPHIA)

Other:1

May 10, 2018

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.30

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.61

PhyloP100

4.9

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Vest4

0.75

MutPred

0.88

Loss of MoRF binding (P = 0.0034);

MVP

0.98

ClinPred

0.49

GERP RS

3.3

PromoterAI

-0.098

Neutral

(source)

Varity_R

0.66

gMVP

0.84

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over