16-173207-G-C

Position:

chr16-173207-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000517.6(HBA2):c.178G>C(p.Gly60Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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. G60D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 17)

Exomes 𝑓: 0.0000078 ( 1 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 7.54

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 16 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, 9 uncertain in NM_000517.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-173208-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 439112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 16-173207-G-C is Pathogenic according to our data. Variant chr16-173207-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.178G>C	p.Gly60Arg	missense_variant	2/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.178G>C	p.Gly60Arg	missense_variant	2/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1 linkuse as main transcript	c.148G>C	p.Gly50Arg	missense_variant	2/2	1
HBA2	ENST00000482565.1 linkuse as main transcript	n.314G>C		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.82G>C	p.Gly28Arg	missense_variant	2/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000305

AC:

AN:

131276

Hom.:

AF XY:

0.0000564

AC XY:

AN XY:

70888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000941

Gnomad SAS exome

AF:

0.000140

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000784

AC:

AN:

1019914

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

517672

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000292

Gnomad4 SAS exome

AF:

0.0000988

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000107

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with HBA2 related disorder (ClinVar ID: VCV000015688, PMID:15658192). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000439112, PMID:8237999). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.934>=0.6, 3CNET: 0.989>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000305). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2023

The HBA2 c.178G>C; p.Gly60Arg variant (Hb Zurich Albisrieden, also known as Gly59Arg, when numbered from the mature protein, rs41328049, HbVar ID: 1199) is an unstable hemoglobin reported in the literatures in a heterozygous individual affected with hypochromic microcytosis with no symptoms (Dutly 2004, also see HbVar and references therein). Notably, homozygosity for this variant (Pedroso 2018) and compound heterozygosity with Southeast Asian deletion (Yang 2016) are associated with alpha thalassemia major or Hb H disease phenotypes. Additionally, the other variant at this codon (c.178G>A; p. Gly60Asp, also known as Hb Adana) has been reported in individuals with Hb H disease and are considered pathogenic (Guruk 1993). This variant is also reported in ClinVar (Variation ID: 15688) and is found in the general population with an overall allele frequency of 0.003% (4/131276 alleles, including 1 homozygote) in the Genome Aggregation Database. The amino acid substitution involves the glycine residue at a structurally critical position significantly affecting the stability of the hemoglobin (Dutly 2004, Scheps 2020, Sharma 2020). The glycine at codon 60 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.934). Based on available information, the p.Gly60Arg variant is considered to be likely pathogenic. References: Curuk MA et al. Hb Adana or alpha 2(59)(E8)Gly-->Asp beta 2, a severely unstable alpha 1-globin variant, observed in combination with the -(alpha)20.5 Kb alpha-thal-1 deletion in two Turkish patients. Am J Hematol. 1993 Dec;44(4):270-5. PMID: 8237999. Dutly F et al. A new highly unstable alpha chain variant causing alpha(+)-thalassemia: Hb Zurich Albisrieden [alpha59(E8)Gly-->Arg (alpha2)]. Hemoglobin. 2004;28(4):347-51. PMID: 15658192. Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Pedroso GA et al. Thalassemia major phenotype caused by HB Zürich-Albisrieden [a2 59(E8) Gly > Arg (HBA2:C.178G > C)] in a Brazilian child. Pediatr Blood Cancer. 2018 Dec;65(12):e27413. PMID: 30151892. Scheps KG et al. Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis. Hum Mutat. 2020 Jan;41(1):81-102. PMID: 31553106. Sharma P et al. HbH disease due to compound heterozygosity for hemoglobins Zürich-Albisrieden and Sallanches. Pediatr Blood Cancer. 2020 Apr;67(4):e28161. PMID: 31930682. Yang X et al. Hydrops Fetalis Associated with Compound Heterozygosity for Hb Zurich-Albisrieden (HBA2: C.178G?>?C) and the Southeast Asian (- -SEA/) Deletion. Hemoglobin. 2016 Sep;40(5):353-355. PMID: 27686733. -

Alpha-thalassemia, Dutch type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

HEMOGLOBIN ZURICH ALBISRIEDEN

Other:1

other, no assertion criteria provided

literature only

OMIM

Oct 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;T

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.82

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.84

MutPred

0.98

Gain of MoRF binding (P = 0.0338);.;

MVP

1.0

MPC

2.7

ClinPred

1.0

GERP RS

4.0

gMVP

0.98

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