rs41344646

chr16-173480-C-Achr16-173480-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PM1 PM2 PP3_Strong BP6_Moderate

The NM_000517.6(HBA2):c.309C>A(p.Ser103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,094 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 Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.877

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000517.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• BP6: Variant 16-173480-C-A is Benign according to our data. Variant chr16-173480-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 15671.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.309C>A	p.Ser103Arg	missense_variant	3/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.309C>A	p.Ser103Arg	missense_variant	3/3	1	NM_000517.6	P1
	ENST00000702607.1			downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458094 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725182

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 03, 2021

- -

HEMOGLOBIN MANITOBA Other:1

other, no assertion criteria provided

literature only

OMIM

May 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.23	N
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	0.73	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.023	D;D
Vest4		0.76
MutPred		0.96		Gain of catalytic residue at S103 (P = 0.0654);.;
MVP		1.0
MPC		1.7
ClinPred		0.96	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.94

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: rs41344646; hg19: chr16-223479;