chr16-173163-C-T

Variant names:

• chr16-173163-C-T
• rs281864830
• NM_000517.6:c.134C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000517.6(HBA2):​c.134C>T​(p.Pro45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 0 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, 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

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_000517.6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.134C>T	p.Pro45Leu	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.134C>T	p.Pro45Leu	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 736598 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 385144

African (AFR) AF: 0.00 AC: 0 AN: 16680

American (AMR) AF: 0.00 AC: 0 AN: 35946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20486

East Asian (EAS) AF: 0.00 AC: 0 AN: 33398

South Asian (SAS) AF: 0.00 AC: 0 AN: 64954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 492108

Other (OTH) AF: 0.00 AC: 0 AN: 35870

GnomAD4 genome Cov.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.36	N
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.27	D
PhyloP100		1.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.076	T;T
Vest4		0.37
MutPred		0.29		Loss of methylation at K41 (P = 0.0812);.;
MVP		0.99
MPC		1.5
ClinPred		0.91	D
GERP RS		2.1
PromoterAI		0.23	Neutral
gMVP		0.81
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs281864830; hg19: chr16-223162;