16-172916-G-C

Variant names:

• chr16-172916-G-C
• rs63751178
• NM_000517.6:c.4G>C

Variant summary

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

The NM_000517.6(HBA2):​c.4G>C​(p.Val2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93

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, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.4G>C	p.Val2Leu	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.4G>C	p.Val2Leu	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.50	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.12	T
Vest4		0.79
MutPred		0.85		Loss of MoRF binding (P = 0.0826);
MVP		0.99
MPC		1.3
ClinPred		0.36	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.61

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: rs63751178; hg19: chr16-222915;