rs33915947

Variant names:

• chr16-177089-G-A
• rs33915947
• NM_000558.5:c.256G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-177089-G-A
• chr16-177089-G-C
• chr16-177089-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000558.5(HBA1):​c.256G>A​(p.Asp86Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000786 in 1,399,382 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D86G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 5.07
• Publications: 6 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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 20 uncertain in NM_000558.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.256G>A	p.Asp86Asn	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.256G>A	p.Asp86Asn	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1399382 Hom.: 0 Cov.: 27 AF XY: 0.0000101 AC XY: 7 AN XY: 693910

African (AFR) AF: 0.00 AC: 0 AN: 32288

American (AMR) AF: 0.00 AC: 0 AN: 39124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25356

East Asian (EAS) AF: 0.00 AC: 0 AN: 37582

South Asian (SAS) AF: 0.00 AC: 0 AN: 82098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4078

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1083158

Other (OTH) AF: 0.00 AC: 0 AN: 58308

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Mar 31, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb G-Norfolk variant (HBA1: c.256G>A; p.Asp86Asn, also known as Asp85Asn when numbered from the mature protein, rs33915947, HbVar ID:129), is reported in the heterozygous state in individuals with no abnormal hematological features (see HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 15731) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant was identified in combination with beta0 thalassemia in two related individuals with microcytosis and hypochromia, but their interaction and pathogenicity are unclear (Kimura 2015). Functional characterization of the variant protein indicates a higher oxygen affinity, but otherwise similar to normal hemoglobin (Cohen-Solal 1975). The aspartic acid at codon 86 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.693). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Cohen-Solal M et al. Haemoglobin G Norfolk alpha 85 (F6) Asp leads to Asn. Structural characterization by sequenator analysis and functional properties of a new variant with high oxygen affinity. FEBS Lett. 1975 Feb 1;50(2):163-7. PMID: 234399. 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. -

HEMOGLOBIN G (NORFOLK) Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.016
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.66	D
PhyloP100		5.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.040	D;D
Sift4G	Benign	0.099	T;T
Vest4		0.47
MutPred		0.78		Loss of ubiquitination at K91 (P = 0.046);.;
MVP		0.96
ClinPred		0.98	D
GERP RS		3.4
PromoterAI		-0.0058	Neutral
Varity_R		0.83
gMVP		0.85

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

Other links and lift over

dbSNP: rs33915947; hg19: chr16-227088;