16-173481-C-T

Position:

• chr16-173481-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H104R) has been classified as Likely benign.

• 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

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.310C>T	p.His104Tyr	missense_variant	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.310C>T	p.His104Tyr	missense_variant	3/3	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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 14, 2024

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

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
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
MutPred		0.97		Gain of ubiquitination at K100 (P = 0.2285);.;
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.86

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: rs63750073; hg19: chr16-223480;