16-173171-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000517.6(HBA2):c.142G>C(p.Asp48His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D48Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 12)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:4

Conservation

PhyloP100: 5.34

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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, 7 uncertain in NM_000517.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 16-173171-G-C is Pathogenic according to our data. Variant chr16-173171-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.142G>C	p.Asp48His	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 link	c.142G>C	p.Asp48His	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1 link	c.109G>C	p.Asp37His	missense_variant	Exon 2 of 2	1		ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1 link	n.278G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1 link	c.46G>C	p.Asp16His	missense_variant	Exon 2 of 3	2		ENSP00000380908.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.0000401

AC:

AN:

99842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00143

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000945

AC:

AN:

126964

Hom.:

AF XY:

0.0000438

AC XY:

AN XY:

68546

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00161

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:

0.000254

GnomAD4 exome

AF:

0.0000416

AC:

AN:

793608

Hom.:

Cov.:

AF XY:

0.0000243

AC XY:

AN XY:

411868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00114

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000736

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000401

AC:

AN:

99842

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

46988

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00143

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000240

Hom.:

ExAC

AF:

0.0000402

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Sep 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Hasharon variant (HBA2 c.142G>C; p.Asp48His variant, also known as Asp47His when numbered from the mature protein, HbVarID: 65, rs281864834, ClinVar Variation ID 15636), also known as Hb Sealy and Hb L-Ferrara, is reported in the literature in multiple families from differing ethnicities affected with anemia and red blood cell disorder (Charache 1969, de la Fuente-Gonzalo 2019, Gilad 2017, Kimura 2015, Nagel 1969, Pich 1978, Schneider 1968, Warghade 2018). Individuals heterozygous for this variant have lower levels of the Hb Hasharon alpha chain than expected (Schneider 1968, Charache 1969), and some have been reported to have microcytosis and hypochromia (Kimura 2015). Functional characterization of Hb Hasharon indicates that the variant alpha chain has reduced stability in vitro (Charache 1969) and in vivo (Molchanova 1994). This variant is found in the general population with an overall allele frequency of 0.009% (12/126964 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL:0.789). Based on available information, the variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Charache S et al. Hemoglobin Hasharon (alpha-2-47 his(CD5)beta-2): a hemoglobin found in low concentration. J Clin Invest. 1969; 48(5):834-47. PMID: 5780195. de la Fuente-Gonzalo F et al. Characterization of deletional and non-deletional alpha globin variants in a large cohort from Spain between 2009 and 2014. Ann Hematol. 2019 Jul. PMID: 31025160. Gilad O et al. Molecular diagnosis of alpha-thalassemia in a multiethnic population. Eur J Haematol. 2017 Jun;98(6):553-562. PMID: 28160324. Kimura E et al. Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. Rev Bras Hematol Hemoter. 2015; 37(2):103-8. PMID: 25818820. 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. Nagel R et al. Hemoglobin L Ferrara in a Jewish family associated with a hemolytic state in the propositus. Blood. 1969; 34(2):157-65. PMID: 5794113. Pich P et al. Interaction between Hb Hasharon and alpha-thalassemia: an approach to the problem of the number of human alpha loci. Blood. 1978; 51(2):339-46. PMID: 620088. Schneider R et al. Hemoglobin sealy (alpha 2-47His-beta 2): a new variant in a Jewish family. Am J Hum Genet. 1968; 20(2):151-6. PMID: 5643179. Warghade S et al. Prevalence of hemoglobin variants and hemoglobinopathies using cation-exchange high-performance liquid chromatography in central reference laboratory of India: A report of 65779 cases. J Lab Physicians. 2018 Jan-Mar. PMID: 29403210. -

Jan 28, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; in-vivo studies show percentage of the mutant Hb decreased with time, supporting instability of the mutant Hb in vivo (Charache et al., 1969); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25818820, 620088, 5643179, 5794113, 5780195, 2752146, 5587575, 28160324, 7803274, 31553106) -

Oct 07, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA2 c.142G>C (p.Asp48His) variant (also known as Hb Hasharon) has been reported in the heterozygous state in individuals with normal clinical presentation (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)) or with microcytic anemia (PMID: 5780195 (1969), 31025160 (2019)). Individuals who are homozygous for this variant presented with microcytosis, hypochromia, and polycythemia (PMID: 25818820 (2015)). This variant has been reported to be mildly unstable in experimental studies (PMID: 5780195 (1969), 7803274 (1994)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

alpha Thalassemia

Pathogenic:2

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBA2 c.142G>C (p.Asp48His), also reported as "hemoglobin Hasharon", "a2 47 his" and "Hasharon [47(CE5)Asp>His]", results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 126964 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HBA2 causing Alpha Thalassemia (9.5e-05 vs 0.0056). c.142G>C has been reported in the literature in multiple bi-allelic or heterozygous individuals affected with Alpha Thalassemia, microcytosis and hypochromia (examples: Gilad_ 2017, Kimura_ 2015, Silva_ 2013). The following publications have been ascertained in the context of this evaluation (PMID: 5780195, 28160324, 25818820, 7803274, 23741188, 20309827). ClinVar contains an entry for this variant (Variation ID: 15636). Based on the evidence outlined above, the variant was classified as pathogenic. -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7

Pathogenic:1

Apr 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HEMOGLOBIN SEALY

Other:1

May 21, 2018

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN L (FERRARA)

Other:1

May 21, 2018

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN SINAI

Other:1

May 21, 2018

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN HASHARON

Other:1

May 21, 2018

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

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

.;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.59

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0060

D;D

Vest4

0.62

MutPred

0.96

Gain of disorder (P = 0.1421);.;

MVP

1.0

MPC

1.9

ClinPred

0.67

GERP RS

3.2

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over