dbSNP rs866267079: HBA1:c.-77C>G (chr16-176640-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000558.5(HBA1):c.-77C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000088 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 upstream_gene

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.91

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]

HBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.-77C>G		upstream_gene_variant		ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
HBA1	ENST00000320868.9 link	c.-77C>G	upstream_gene_variant	1	NM_000558.5	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1 link	n.-58C>G	upstream_gene_variant	1
HBA1	ENST00000487791.1 link	n.-108C>G	upstream_gene_variant	1
HBA1	ENST00000397797.1 link	c.-124C>G	upstream_gene_variant	2		ENSP00000380899.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152236

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000882

AC:

124

AN:

1406684

Hom.:

Cov.:

AF XY:

0.0000760

AC XY:

AN XY:

697440

show subpopulations

Gnomad4 AFR exome

AF:

0.00294

Gnomad4 AMR exome

AF:

0.000183

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:

0.00000185

Gnomad4 OTH exome

AF:

0.000378

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000630

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00219

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 17, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA1 c.-77C>G variant is located 77 bp upstream of the translation initiation codon in the promoter region of the alpha1-globin gene. To the best of our knowledge, this variant has not been reported in individuals with HBA1-related conditions in the published literature. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.16

DANN

Benign

0.50

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over