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rs33944368

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000558.5(HBA1):c.143A>C(p.Asp48Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D48G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Consequence

HBA1
NM_000558.5 missense

Scores

8
6
4

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 3.37
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBA1NM_000558.5 linkuse as main transcriptc.143A>C p.Asp48Ala missense_variant 2/3 ENST00000320868.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBA1ENST00000320868.9 linkuse as main transcriptc.143A>C p.Asp48Ala missense_variant 2/31 NM_000558.5 P1
HBA1ENST00000472694.1 linkuse as main transcriptn.279A>C non_coding_transcript_exon_variant 1/21
HBA1ENST00000487791.1 linkuse as main transcriptn.112A>C non_coding_transcript_exon_variant 2/21
HBA1ENST00000397797.1 linkuse as main transcriptc.47A>C p.Asp16Ala missense_variant 2/32

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
15
GnomAD4 genome
Cov.:
30

ClinVar

Significance: other
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

HEMOGLOBIN CORDELE Other:1
other, no assertion criteria providedliterature onlyOMIMJul 20, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Benign
0.32
T;.
Eigen
Benign
-0.021
Eigen_PC
Benign
-0.066
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.76
D
MutationTaster
Benign
0.78
D;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-7.6
D;D
REVEL
Uncertain
0.60
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Vest4
0.57
MutPred
0.86
Loss of disorder (P = 0.1538);.;
MVP
0.99
ClinPred
1.0
D
GERP RS
3.2
Varity_R
0.95
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs33944368; hg19: chr16-226975; API