Genetic Variant HBA1:p.Ser82Cys (chr16-177078-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The NM_000558.5(HBA1):c.245C>G(p.Ser82Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,386,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000010 ( 2 hom. )

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 0.883

Publications

2 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 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 30 uncertain in NM_000558.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.245C>G	p.Ser82Cys	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.245C>G	p.Ser82Cys	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000476

AC:

AN:

147032

AF XY:

0.0000623

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

1386962

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

687634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31960

American (AMR)

AF:

0.00

AC:

AN:

38288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25266

East Asian (EAS)

AF:

0.00

AC:

AN:

37162

South Asian (SAS)

AF:

0.000172

AC:

AN:

81484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4060

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074520

Other (OTH)

AF:

0.00

AC:

AN:

57918

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

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.:

ExAC

AF:

0.0000177

AC:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN NIGERIA

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

Benign

0.28

BayesDel_addAF

Benign

-0.0016

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.81

PhyloP100

0.88

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.037

D;T

Vest4

0.54

MutPred

0.80

Loss of disorder (P = 0.0063);.;

MVP

1.0

ClinPred

0.72

GERP RS

3.3

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.83

gMVP

0.90

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