rs35994191

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000558.5(HBA1):​c.407T>A​(p.Val136Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: not found (cov: 32)

Consequence

HBA1
NM_000558.5 missense

Scores

8
5
5

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 0.379
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000558.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBA1NM_000558.5 linkuse as main transcriptc.407T>A p.Val136Glu missense_variant 3/3 ENST00000320868.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBA1ENST00000320868.9 linkuse as main transcriptc.407T>A p.Val136Glu missense_variant 3/31 NM_000558.5 P1
HBA1ENST00000472694.1 linkuse as main transcriptn.543T>A non_coding_transcript_exon_variant 2/21
ENST00000702457.1 linkuse as main transcriptn.102A>T non_coding_transcript_exon_variant 1/1
HBA1ENST00000397797.1 linkuse as main transcriptc.311T>A p.Val104Glu missense_variant 3/32

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

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

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.65
D;.
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.84
T;T
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
0.66
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.080
T;D
Vest4
0.71
MutPred
0.70
Gain of disorder (P = 0.007);.;
MVP
1.0
ClinPred
0.98
D
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.3
Varity_R
0.94
gMVP
0.98

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: rs35994191; hg19: chr16-227388; API