16-176740-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM2PP3_StrongBP6_Moderate

The NM_000558.5(HBA1):ā€‹c.24G>Cā€‹(p.Lys8Asn) 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 Likely benign (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K8E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)
Exomes š‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

5
8
5

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 3.19
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
BP6
Variant 16-176740-G-C is Benign according to our data. Variant chr16-176740-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 15861.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HBA1NM_000558.5 linkuse as main transcriptc.24G>C p.Lys8Asn missense_variant 1/3 ENST00000320868.9 NP_000549.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HBA1ENST00000320868.9 linkuse as main transcriptc.24G>C p.Lys8Asn missense_variant 1/31 NM_000558.5 ENSP00000322421 P1
HBA1ENST00000472694.1 linkuse as main transcriptn.43G>C non_coding_transcript_exon_variant 1/21
HBA1ENST00000397797.1 linkuse as main transcriptc.-24G>C 5_prime_UTR_variant 1/32 ENSP00000380899
HBA1ENST00000487791.1 linkuse as main transcript upstream_gene_variant 1

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1435924
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
712850
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
28

ClinVar

Significance: Likely benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 27, 2021- -
HEMOGLOBIN TATRAS Other:1
other, no assertion criteria providedliterature onlyOMIMJul 20, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.41
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.84
T
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.55
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.9
D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0050
D
Sift4G
Pathogenic
0.0010
D
Vest4
0.72
MutPred
0.97
Loss of methylation at K8 (P = 0.0143);
MVP
0.96
ClinPred
0.96
D
GERP RS
2.5
Varity_R
0.92
gMVP
0.92

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: rs34410516; hg19: chr16-226739; API