chr16-173229-T-C

Position:

• chr16-173229-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_000517.6(HBA2):​c.200T>C​(p.Leu67Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.47

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 16-173229-T-C is Pathogenic according to our data. Variant chr16-173229-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15669.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.200T>C	p.Leu67Pro	missense_variant	2/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.200T>C	p.Leu67Pro	missense_variant	2/3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.167T>C	p.Leu56Pro	missense_variant	2/2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.336T>C		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.104T>C	p.Leu35Pro	missense_variant	2/3	2		ENSP00000380908.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 20

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

alpha Thalassemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 22, 2024

Variant summary: HBA2 c.200T>C (p.Leu67Pro), also known as Hb Dartmouth, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 133748 control chromosomes (gnomAD). c.200T>C has been reported in the literature in individuals affected with Hb H disease with severe anemia that required transfusions. One pair of twins was heterozygous with the variant and a southeast asian deletion of HBA1 and HBA2 in trans (McBride_2001), while another case was homozygous for the variant without an HBA1 variant reported (Farashi_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11791870, 25976777). ClinVar contains an entry for this variant (Variation ID: 15669). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

HEMOGLOBIN DARTMOUTH Other:1

other, no assertion criteria provided

literature only

OMIM

Oct 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.72	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.95
MutPred		0.94		Loss of stability (P = 0.0062);.;
MVP		1.0
MPC		3.2
ClinPred		1.0	D
GERP RS		4.2
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs41323248; hg19: chr16-223228;