chr16-176717-AT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_000558.5(HBA1):​c.2del​(p.Met1?) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 28)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 frameshift, start_lost

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.48
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 Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.995 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-176717-AT-A is Pathogenic according to our data. Variant chr16-176717-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1162201.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.2del p.Met1? frameshift_variant, start_lost 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.2del p.Met1? frameshift_variant, start_lost 1/31 NM_000558.5 ENSP00000322421 P1
HBA1ENST00000472694.1 linkuse as main transcriptn.21del non_coding_transcript_exon_variant 1/21
HBA1ENST00000397797.1 linkuse as main transcriptc.-46del 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: AS_VQSR
AF:
6.88e-7
AC:
1
AN:
1454218
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
722990
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000254
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
Bravo
AF:
0.00000756

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

alpha Thalassemia Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingNxGen MDxDec 30, 2019This null variant (c.2del) is predicted to result in start loss in a gene where loss-of-function is a known mechanism of disease (PVS1). This variant is not found in gnomAD databases (PM2) and is not referenced in the literature. An alternate variant that results in the loss of the initiator methionine, c.2T>A, p.Met1Lys, has been described by Waye et al. (PMID: 27821014) and Shang et al. (PMID 28865746) in association with alpha thalassemia. We interpret c.2del to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

LitVar

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

Other links and lift over

dbSNP: rs1298047912; hg19: chr16-226716; API