16-173286-A-T

Variant names:

• chr16-173286-A-T
• rs41331747
• NM_000517.6:c.257A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1 PM2 PP3_Strong BP6

The NM_000517.6(HBA2):​c.257A>T​(p.Asp86Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,388,416 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. D86G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1 O:1
• Conservation: PhyloP100: 5.52
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 8 uncertain in NM_000517.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• BP6: Variant 16-173286-A-T is Benign according to our data. Variant chr16-173286-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15639.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.257A>T	p.Asp86Val	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.257A>T	p.Asp86Val	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388416 Hom.: 0 Cov.: 27 AF XY: 0.00000145 AC XY: 1 AN XY: 689334

African (AFR) AF: 0.00 AC: 0 AN: 28082

American (AMR) AF: 0.00 AC: 0 AN: 39866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 37854

South Asian (SAS) AF: 0.00 AC: 0 AN: 79988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3990

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1078094

Other (OTH) AF: 0.00 AC: 0 AN: 57546

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jun 26, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Inkster variant (HBA2: c.257A>T; p.Asp86Val, also known as Asp85Val when numbered from the mature protein, rs41331747, HbVar ID: 131) has been reported in an individual with polycythemia (Aguinaga 2000), but has has not been associated with significant clinical symptoms (Reed 1974, HbVar database and references therein). This variant is reported as a stable hemoglobin variant with increased oxygen affinity (Molchanova 1994). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be likely benign. References: Link to HbVar database for Hb Inkster: https://globin.bx.psu.edu/hbvar/hbvar.html Aguinaga M et al. Hb Inkster [alpha85(F6)Asp-->Val] found in a caucasian male with polycythemia. Hemoglobin. 2000; 24(4):333-9. PMID: 11186265. Molchanova T et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994; 88(2):300-6. PMID: 7803274. Reed R et al. Haemoglobin inkster (alpha2 85aspartic acid leads to valine beta2) coexisting with beta-thalassaemia in a Caucasian family. Br J Haematol. 1974; 26(3):475-84. PMID: 4212045. -

Erythrocytosis, familial, 7 Pathogenic:1

Nov 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN INKSTER Other:1

Sep 15, 2023

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.85	D
PhyloP100		5.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.050	T;T
Vest4		0.73
MutPred		0.87		Loss of disorder (P = 0.0301);.;
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		-0.061	Neutral
gMVP		0.92
Mutation Taster		=4/96	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: rs41331747; hg19: chr16-223285;