rs63750294

Variant names:

• chr16-172967-G-C
• rs63750294
• NM_000517.6:c.55G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_Moderate BP6

The NM_000517.6(HBA2):​c.55G>C​(p.Gly19Arg) 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G19D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 2)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.69

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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• BP6: Variant 16-172967-G-C is Benign according to our data. Variant chr16-172967-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330147.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.55G>C	p.Gly19Arg	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.55G>C	p.Gly19Arg	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.22G>C	p.Gly8Arg	missense_variant	Exon 1 of 2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.74G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1	c.-2+9G>C		intron_variant	Intron 1 of 2	2		ENSP00000380908.1

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Oct 06, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBA2 c.55G>C (p.Gly19Arg) results in a non-conservative amino acid change located in the Hemoglobin alpha, zeta, mu, theta, and related Hb subunits domain (IPR002338) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 53364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.55G>C has been reported in the literature in an individual showing no clinical abnormalities of Alpha Thalassemia (Griffiths_1977). These report(s) do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 852596). ClinVar contains an entry for this variant (Variation ID: 1330147). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Mar 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.44	N
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.76	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.29	T
Vest4		0.80
MutPred		0.18		Gain of MoRF binding (P = 0.0187);
MVP		0.99
MPC		1.7
ClinPred		0.95	D
GERP RS		3.8
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs63750294; hg19: chr16-222966;