rs281864895

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000558.5(HBA1):c.178G>A(p.Gly60Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000134 in 149,440 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 Uncertain significance (★★). 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: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.10

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: Likely_pathogenic. The variant received 8 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, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.178G>A	p.Gly60Ser	missense_variant	Exon 2 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.178G>A	p.Gly60Ser	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5		P69905

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149440

Hom.:

Cov.:

show subpopulations

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:

0.0000148

Gnomad OTH

AF:

0.000500

GnomAD2 exomes

AF:

0.00000736

AC:

AN:

135930

AF XY:

0.0000135

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:

0.0000188

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000336

AC:

AN:

1188900

Hom.:

Cov.:

AF XY:

0.00000503

AC XY:

AN XY:

596430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27716

American (AMR)

AF:

0.00

AC:

AN:

36358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23974

East Asian (EAS)

AF:

0.00

AC:

AN:

35268

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3700

European-Non Finnish (NFE)

AF:

0.00000334

AC:

AN:

898174

Other (OTH)

AF:

0.00

AC:

AN:

51258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149440

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72808

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40274

American (AMR)

AF:

0.00

AC:

AN:

14994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5080

South Asian (SAS)

AF:

0.00

AC:

AN:

4564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67480

Other (OTH)

AF:

0.000500

AC:

AN:

2000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb Parma variant (HBA1 c.178G>A; p.Gly60Ser variant, also known as Gly59Ser when numbered from the mature protein, rs281864895, HbVar ID: 2581, ClinVar ID: 993066) to our knowledge, is not reported in the medical literature but is reported in an asymptomatic individual in the HbVar database (see HbVar database link). However, other variants at this codon in the homologous HBA2 gene (Hb Adana; c.179G>A;p.Gly60Asp and Hb Zurich Albisrieden; c.178G>C; p.Gly60Arg) have been reported in affected individuals are considered disease causing (Curuk 1993, Dutly 2004, see HbVar database and references therein). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.899). However, given the lack of clinical and functional data, the significance of p.Gly60Ser variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Curuk MA et al. Hb Adana or alpha 2(59)(E8)Gly-->Asp beta 2, a severely unstable alpha 1-globin variant, observed in combination with the -(alpha)20.5 Kb alpha-thal-1 deletion in two Turkish patients. Am J Hematol. 1993 Dec;44(4):270-5. PMID: 8237999. Dutly F et al. A new highly unstable alpha chain variant causing alpha(+)-thalassemia: Hb Zurich Albisrieden [alpha59(E8)Gly-->Arg (alpha2)]. Hemoglobin. 2004;28(4):347-51. PMID: 15658192. -

Mar 21, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

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

0.90

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.85

PhyloP100

6.1

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.93

MutPred

0.92

Gain of disorder (P = 0.0749);.;

MVP

1.0

ClinPred

0.99

GERP RS

4.3

PromoterAI

-0.0016

Neutral

(source)

Varity_R

0.94

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

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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