rs281865560

Variant names:

• chr16-176763-G-A
• rs281865560
• NM_000558.5:c.47G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BP6

The NM_000558.5(HBA1):​c.47G>A​(p.Gly16Asp) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G16C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.15
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Heinz body anemia

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000294436 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• BP6: Variant 16-176763-G-A is Benign according to our data. Variant chr16-176763-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 618155. Variant chr16-176763-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 618155. Variant chr16-176763-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 618155. Variant chr16-176763-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 618155.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.47G>A	p.Gly16Asp	missense_variant	Exon 1 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.47G>A	p.Gly16Asp	missense_variant	Exon 1 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000599 AC: 1 AN: 166932 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2 AN: 1437472 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 713816

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32482

American (AMR) AF: 0.00 AC: 0 AN: 41936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 38680

South Asian (SAS) AF: 0.00 AC: 0 AN: 83074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4450

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100336

Other (OTH) AF: 0.00 AC: 0 AN: 59368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Apr 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb I-Interlaken variant (HBA1: c.47G>A; p.Gly16Asp, also known as Hb J-Oxford, Hb N-Cosenza, or as Gly15Asp when numbered from the mature protein; rs281865560, HbVar ID: 17) has been described as a stable hemoglobin variant with normal oxygen affinity that did not ameliorate the phenotype of an individual with beta thalassemia major (Guida 2006, Kimura 2015, Molchanova 1994, Schiliro 1976, see HbVar link). The Hb I-Interlaken variant is found on a single chromosome (1/196618 alleles) in the Genome Aggregation Database. The glycine at codon 15 is weakly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.526). Based on the available information, this variant is considered to be likely benign. References: Link to HbVar database for Hb I-Interlaken: https://globin.bx.psu.edu/hbvar/hbvar.html Guida V et al. Hematologic and molecular characterization of a Sicilian cohort of alpha thalassemia carriers. Haematologica. 2006 Mar;91(3):409-10. PMID: 16503552. Kimura EM et al. Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. Rev Bras Hematol Hemoter. 2015 Mar-Apr;37(2):103-8. PMID: 25818820. Molchanova TP et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 Oct;88(2):300-6. PMID: 7803274. Schiliro G et al. A new alkali-resistant hemoglobin alpha2J Oxford gammaF2 in a Sicilian baby girl with homozygous beta0 thalassemia. Blood. 1976 Nov;48(5):639-51. PMID: 10024. -

Apr 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000012 (1/196618 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Individuals heterozygous for this variant have a normal clinical presentation with the variant accounting for 16-23% of the total hemoglobin. In the published literature, the variant has been reported in clinically and hematologically normal carriers or with traits as a result of carrying another pathogenic variant in the beta-globin gene (PMIDs: 10024 (1976), 2666359 (1989), 7803274 (1994)). Functional studies have shown the variant to be stable with normal oxygen affinity (PMID: 10024 (1976)). 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
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	1.9
DANN	Benign	0.83
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.25	T
PhyloP100		-3.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.53
Sift	Benign	0.26	T
Sift4G	Benign	0.50	T
Vest4		0.71
MutPred		0.83		Loss of MoRF binding (P = 0.0422);
MVP		1.0
ClinPred		0.10	T
GERP RS		-8.9
PromoterAI		-0.049	Neutral
Varity_R		0.19
gMVP		0.80
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs281865560; hg19: chr16-226762;