16-173207-G-C

Variant names:

• chr16-173207-G-C
• rs41328049
• NM_000517.6:c.178G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_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. G60V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000078 (1 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• 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 rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.178G>C	p.Gly60Arg	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.178G>C	p.Gly60Arg	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.145G>C	p.Gly49Arg	missense_variant	Exon 2 of 2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.314G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1	c.82G>C	p.Gly28Arg	missense_variant	Exon 2 of 3	2		ENSP00000380908.1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD3 exomes AF: 0.0000305 AC: 4 AN: 131276 Hom.: 1 AF XY: 0.0000564 AC XY: 4 AN XY: 70888

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: 8 AN: 1019914 Hom.: 1 Cov.: 14 AF XY: 0.0000116 AC XY: 6 AN XY: 517672

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.: 17

ExAC AF: 0.0000107 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

alpha Thalassemia Pathogenic:1

Mar 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN ZURICH ALBISRIEDEN Other:1

Oct 13, 2016

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	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.75	T
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	D
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

Other links and lift over

dbSNP: rs41328049; hg19: chr16-223206;