rs41479347

chr16-173540-C-Achr16-173540-C-Gchr16-173540-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000517.6(HBA2):c.369C>A(p.His123Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 25)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.38

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_000517.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.369C>A	p.His123Gln	missense_variant	3/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.369C>A	p.His123Gln	missense_variant	3/3	1	NM_000517.6	P1
HBA2	ENST00000482565.1	n.505C>A		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1	n.121G>T		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1	c.273C>A	p.His91Gln	missense_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248160 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain: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 08, 2023

Variant summary: HBA2 c.369C>A (p.His123Gln) results in a non-conservative amino acid change located in the Globin (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248160 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Another variant resulting in the same amino acid change (c.369C>G) known as Hb Westmead has been reported in the literature in individuals affected with Alpha Thalassemia without strong evidence of causality, and this variant occurs frequently in mainland China (e.g. Xiong_2010, Jiang_2020). These reports do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. 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: 20412082, 32436451). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, although the Hb Westmead variant was classified as uncertain significance (n=4) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Benign	8.0
Dann	Benign	0.97
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.20	N
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.18	T;T
Vest4		0.41
MutPred		0.88		Gain of ubiquitination at K128 (P = 0.1103);.;
MVP		1.0
MPC		2.4
ClinPred		0.96	D
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
gMVP		0.85

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: rs41479347; hg19: chr16-223539;