rs41518249

Positions:

• chr16-173179-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000517.6(HBA2):​c.150C>A​(p.Ser50Arg) 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S50N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.341

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000517.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.150C>A	p.Ser50Arg	missense_variant	2/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.150C>A	p.Ser50Arg	missense_variant	2/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1	c.120C>A	p.Ser40Arg	missense_variant	2/2	1
HBA2	ENST00000482565.1	n.286C>A		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.54C>A	p.Ser18Arg	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000120 AC: 1 AN: 835174 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 431174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000172

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 19, 2022

- -

HEMOGLOBIN SAVARIA Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	.;T
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.32	N
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.10	T;T
Vest4		0.68
MutPred		0.64		Gain of solvent accessibility (P = 0.0155);.;
MVP		1.0
MPC		2.3
ClinPred		0.99	D
GERP RS		3.2
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41518249; hg19: chr16-223178;