rs63750073

Variant names:

• chr16-173481-C-T
• rs63750073
• NM_000517.6:c.310C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000517.6(HBA2):​c.310C>T​(p.His104Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H104R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 5.36
• 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, 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: Pathogenic. The variant received 10 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, 9 uncertain in NM_000517.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-173482-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 993106.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.310C>T	p.His104Tyr	missense_variant	Exon 3 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.310C>T	p.His104Tyr	missense_variant	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBA2 c.310C>T (p.His104Tyr) results in a conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248064 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.310C>T has been reported in the literature in the heterozygous state in individuals with mild anemia (e.g. Guida_2006, Hoyer_2002, Lucan_1999). These report(s) do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. At least one publication reports experimental evidence that this variant inhibits binding to Beta globin and AHSP, however, does not allow convincing conclusions about the variant effect (e.g. Yu_2009). This variant is also known as Hb Lombard, Hb Charolles, and H103Y. The following publications have been ascertained in the context of this evaluation (PMID: 16503552, 12144061, 10569723, 19349619). ClinVar contains an entry for this variant (Variation ID: 15673). Based on the evidence outlined above, the variant was classified as uncertain significance.

HEMOGLOBIN LOMBARD Other:1

Mar 28, 2013

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.0	.;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	0.0	.;.
PhyloP100		5.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.027	D;D
Vest4		0.64
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.86
Mutation Taster		=13/87	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: rs63750073; hg19: chr16-223480;