NM_000558.5:c.179G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000558.5(HBA1):c.179G>A(p.Gly60Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G60V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 6.10

Publications

31 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: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-177011-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 993066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 16-177012-G-A is Pathogenic according to our data. Variant chr16-177012-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 15849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.179G>A	p.Gly60Asp	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9 link	c.179G>A	p.Gly60Asp	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000420

AC:

AN:

1190478

Hom.:

Cov.:

AF XY:

0.00000335

AC XY:

AN XY:

596968

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27750

American (AMR)

AF:

0.00

AC:

AN:

36262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23984

East Asian (EAS)

AF:

0.00

AC:

AN:

35250

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3702

European-Non Finnish (NFE)

AF:

0.00000111

AC:

AN:

900002

Other (OTH)

AF:

0.0000585

AC:

AN:

51262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Pathogenic:2

May 29, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HBA1 c.179G>A (p.Gly60Asp) 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 variant was absent in 135930 control chromosomes. c.179G>A has been reported in the literature in multiple individuals affected with Alpha Thalassemia (example, Bayat_2013, Tamaddoni_2009). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.178G>C, p.Gly60Arg), supporting the critical relevance of codon 60 to HBA1 protein function. 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: 23402770, 19373587). ClinVar contains an entry for this variant (Variation ID: 15849). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 02, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Mar 19, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/165308 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Jun 18, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hemoglobin H disease, nondeletional

Pathogenic:1

Jul 20, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693798:Methemoglobinemia, alpha type;C4693823:Erythrocytosis, familial, 7

Pathogenic:1

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HEMOGLOBIN ADANA

Other:1

Jul 20, 2016

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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

0.99

PhyloP100

6.1

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.96

MutPred

0.99

Gain of ubiquitination at K62 (P = 0.0525);.;

MVP

1.0

ClinPred

1.0

GERP RS

4.3

PromoterAI

0.047

Neutral

(source)

Varity_R

0.98

gMVP

0.99

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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