rs111033604

chr16-172942-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000517.6(HBA2):c.30C>G(p.Asn10Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. N10T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 1)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: -2.20

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.30C>G	p.Asn10Lys	missense_variant	1/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.30C>G	p.Asn10Lys	missense_variant	1/3	1	NM_000517.6	P1
HBA2	ENST00000482565.1	n.49C>G		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-18C>G		5_prime_UTR_variant	1/3	2
HBA2	ENST00000484216.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 1

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

alpha Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 16, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 27, 2020

The Hb Park Ridge variant (HBA2: c.30C>G; p.Asn10Lys, also known as Asn9Lys when numbered from the mature protein, rs111033604) is reported in the literature in the heterozygous state in a healthy individual with normal hematology (Hoyer 2002, HbVar database). However, the phenotype of this variant in the presence of other alpha globin variants is unknown. The Hb Park Ridge variant is reported in ClinVar (Variation ID: 15650), but is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). The asparagine at residue 9 is weakly conserved, and computational algorithms (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the Asn9Lys variant is uncertain at this time. References: Link to HbVar database for Hb Park Ridge: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=914 Hoyer JD et al. Four new variants of the alpha2-globin gene without clinical or hematologic effects: Hb Park Ridge (alpha9(alpha7)Asn-->Lys (alpha2)), Hb Norton (alpha72(EF1)His-->Asp (alpha2)), Hb Lombard (alpha103(G10)His-->Tyr (alpha2)), and Hb San Antonio (A113(GH2)Leu-->Arg (A2)). Hemoglobin. 2002 May;26(2):175-9. -

HEMOGLOBIN PARK RIDGE Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.15	N
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.92	T
Vest4		0.88
MutPred		0.96		Gain of MoRF binding (P = 0.0221);
MVP		1.0
MPC		1.5
ClinPred		0.48	T
GERP RS		-0.060
gMVP		0.92

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

Other links and lift over

dbSNP: rs111033604; hg19: chr16-222941;