Genetic Variant HBA1:p.Ala72Glu (chr16-177048-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000558.5(HBA1):c.215C>A(p.Ala72Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,330,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A72V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: -5.26

Publications

3 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29381287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.215C>A	p.Ala72Glu	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.215C>A	p.Ala72Glu	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1330330

Hom.:

Cov.:

AF XY:

0.00000303

AC XY:

AN XY:

660538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30588

American (AMR)

AF:

0.00

AC:

AN:

36622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24814

East Asian (EAS)

AF:

0.00

AC:

AN:

36002

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3982

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1027726

Other (OTH)

AF:

0.00

AC:

AN:

55988

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

GnomAD4 genome

Cov.:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN J (HABANA)

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

0.13

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

0.022

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.084

T;.

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.55

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.29

T;T

MetaSVM

Uncertain

0.099

PhyloP100

-5.3

PrimateAI

Benign

0.47

PROVEAN

Benign

0.57

N;N

REVEL

Uncertain

0.47

Sift

Benign

0.070

T;T

Sift4G

Benign

0.46

T;T

Vest4

0.39

MutPred

0.48

Gain of disorder (P = 0.111);.;

MVP

0.99

ClinPred

0.15

GERP RS

-8.6

PromoterAI

0.0049

Neutral

(source)

Varity_R

0.33

gMVP

0.72

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over