NM_000517.6:c.309C>A

Variant names:

• chr16-173480-C-A
• rs41344646
• NM_000517.6:c.309C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 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 the same amino acid substitution has been previously reported as Likely benign in 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
• Publications: 2 publications found

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]

HBA2 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Heinz body anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• unstable hemoglobin disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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 VariationId is 15671.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.309C>A	p.Ser103Arg	missense	Exon 3 of 3	NP_000508.1	D1MGQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.309C>A	p.Ser103Arg	missense	Exon 3 of 3	ENSP00000251595.6	P69905
	HBA2	ENST00000482565.1	TSL:1	n.445C>A		non_coding_transcript_exon	Exon 2 of 2
	HBA2	ENST00000397806.1	TSL:2	c.213C>A	p.Ser71Arg	missense	Exon 3 of 3	ENSP00000380908.1	G3V1N2

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

African (AFR) AF: 0.00 AC: 0 AN: 31346

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	-	HEMOGLOBIN MANITOBA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
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
MetaSVM	Uncertain	0.25	D
PhyloP100		-0.88
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.023	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

Other links and lift over

dbSNP: rs41344646; hg19: chr16-223479;