chr16-176735-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000558.5(HBA1):​c.19G>C​(p.Asp7His) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D7A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)

Consequence

HBA1
NM_000558.5 missense

Scores

11
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.77
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.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HBA1NM_000558.5 linkuse as main transcriptc.19G>C p.Asp7His 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.19G>C p.Asp7His missense_variant 1/31 NM_000558.5 ENSP00000322421 P1
HBA1ENST00000472694.1 linkuse as main transcriptn.38G>C non_coding_transcript_exon_variant 1/21
HBA1ENST00000397797.1 linkuse as main transcriptc.-29G>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
Cov.:
29
GnomAD4 genome
Cov.:
28

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 21, 2020The Hb Galliera I variant (HBA1: c.19G>C; p.Asp7His, also known as Asp6His when numbered from the mature protein; rs33961916) has been reported in a heterozygous state in individuals with no clinical symptoms (HbVar database). However, the phenotype of this variant in the presence of pathogenic globin variants is unknown. The p.Asp7His variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartate at residue 6 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant is deleterious. Due to limited information, the clinical significance of the Hb Galliera I variant is uncertain at this time. References: Link to HbVar database for Hb Galliera I: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2578 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.69
D
Eigen
Benign
0.16
Eigen_PC
Benign
0.11
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Pathogenic
0.97
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-5.3
D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Vest4
0.71
MutPred
0.47
Gain of MoRF binding (P = 0.0158);
MVP
1.0
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.98
gMVP
0.87

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: rs33961916; hg19: chr16-226734; API