chr16-173550-G-A

Position:

• chr16-173550-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000517.6(HBA2):​c.379G>A​(p.Asp127Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D127G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 O:1
• Conservation: PhyloP100: 7.04

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 chr16-173550-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 439117.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 16-173550-G-A is Pathogenic according to our data. Variant chr16-173550-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15662.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.379G>A	p.Asp127Asn	missense_variant	3/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.379G>A	p.Asp127Asn	missense_variant	3/3	1	NM_000517.6	P1
HBA2	ENST00000482565.1	n.515G>A		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1	n.111C>T		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1	c.283G>A	p.Asp95Asn	missense_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248750 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459020 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 10, 2022	The Hb Tarrant variant (HBA2: c.379G>A; p.Asp127Asn, also known as Asp126Asn when numbered from the mature protein, rs33933481, HbVar ID: 188) has been described in healthy individuals or individuals with mild erythrocytosis as a heterozygote and more severe erythrocytosis as a homozygote (Ibarra 1981, Ip 2016, HbVar database). The aspartate at residue 127 is located at the alpha1-alpha2 interface and forms salt bridges with Arg142 on the opposite dimer (Wajcman 2005). Variants in this region commonly lead to high oxygen affinity and reduced cooperativity (Wajcman 2005), which has been observed for the Hb Tarrant variant (Moo-Penn 1977). This variant is reported in ClinVar (Variation ID: 15662) and is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic dominant for mild erythrocytosis. References: Link to variant in HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Ibarra B et al. Heterozygosity and homozygosity for the high oxygen affinity hemoglobin Tarrant or alpha 126 (H9) Asp replaced by Asn in two Mexican families. Hemoglobin. 1981;5(4):337-48. PMID: 7019159. Ip KL et al. Hb Tarrant (a126(H9)Asp?Asn; HBA2: c.379G?>?A (or HBA1)) in a Chinese Family as a Cause of Familial Erythrocytosis. Hemoglobin. 2016 Aug;40(4):260-3. PMID: 27240426. Moo-Penn WF et al. Hemoglobin Tarrant: alpha126(H9) Asp leads to Asn. A new hemoglobin variant in the alpha1beta1 contact region showing high oxygen affinity and reduced cooperativity. Biochim Biophys Acta. 1977 Feb 22;490(2):443-51. PMID: 13856. Wajcman H et al. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106. PMID: 15921161. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 09, 2020	The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism. The variant predicted to have a damaging effect on the protein. -

HEMOGLOBIN TARRANT 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	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.023	D;D
Vest4		0.82
MutPred		0.95		Gain of MoRF binding (P = 0.0612);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.2
gMVP		0.84

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: rs33933481; hg19: chr16-223549;