NM_000517.6:c.89T>C

Variant names:

• chr16-173001-T-C
• rs41341344
• NM_000517.6:c.89T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_000517.6(HBA2):​c.89T>C​(p.Leu30Pro) 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 3)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.95
• Publications: 1 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_000517.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-173001-T-C is Pathogenic according to our data. Variant chr16-173001-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 15651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.89T>C	p.Leu30Pro	missense	Exon 1 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.89T>C	p.Leu30Pro	missense	Exon 1 of 3	ENSP00000251595.6	P69905
	HBA2	ENST00000484216.1	TSL:1	c.56T>C	p.Leu19Pro	missense	Exon 1 of 2	ENSP00000495899.1	A0A2R8Y7C0
	HBA2	ENST00000482565.1	TSL:1	n.108T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD4 exome AF: 0.00000228 AC: 1 AN: 437880 Hom.: 0 Cov.: 0 AF XY: 0.00000434 AC XY: 1 AN XY: 230538

African (AFR) AF: 0.00 AC: 0 AN: 10900

American (AMR) AF: 0.00 AC: 0 AN: 20144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13554

East Asian (EAS) AF: 0.00 AC: 0 AN: 30030

South Asian (SAS) AF: 0.00 AC: 0 AN: 45506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1872

European-Non Finnish (NFE) AF: 0.00000381 AC: 1 AN: 262226

Other (OTH) AF: 0.00 AC: 0 AN: 25032

GnomAD4 genome Cov.: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	alpha Thalassemia (1)
1	-	-	Hemoglobin H disease, nondeletional (1)
-	-	-	HEMOGLOBIN AGRINIO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		2.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.93
MutPred		0.94		Gain of glycosylation at L30 (P = 0.0144)
MVP		1.0
MPC		3.2
ClinPred		1.0	D
GERP RS		3.9
PromoterAI		0.070	Neutral
gMVP		1.0
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41341344; hg19: chr16-223000;