16-172981-C-T

Variant names:

• chr16-172981-C-T
• rs63751457
• NM_000517.6:c.69C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_000517.6(HBA2):​c.69C>T​(p.Gly23Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 2)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: HBA2 NM_000517.6 synonymous
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -3.95

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 10 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-172981-C-T is Pathogenic according to our data. Variant chr16-172981-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15687.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.69C>T	p.Gly23Gly	synonymous_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.69C>T	p.Gly23Gly	synonymous_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.36C>T	p.Gly12Gly	synonymous_variant	Exon 1 of 2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.88C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1	c.-2+23C>T		intron_variant	Intron 1 of 2	2		ENSP00000380908.1

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD3 exomes AF: 0.0000374 AC: 2 AN: 53542 Hom.: 0 AF XY: 0.0000371 AC XY: 1 AN XY: 26986

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000262 AC: 11 AN: 419174 Hom.: 0 Cov.: 0 AF XY: 0.0000363 AC XY: 8 AN XY: 220470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000180

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000125

GnomAD4 genome Cov.: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA2 c.69C>T (p.Gly23=) synonymous variant (also known as Codon 22 C>T) is predicted to interfere with normal splicing of the HBA2 mRNA (PMID: 15481895 (2004)). In the published literature, this variant has been reported as being associated with alpha(+)-thalassemia (PMID: 15481895 (2004), 20642338 (2010), 23614625 (2013), 26365411 (2015), 36567661 (2023), 37033172 (2023)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on HBA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, this variant is classified as likely pathogenic. -

Nov 20, 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.69C>T; Gly22Gly variant (rs63751457, HbVar ID: 2514), also known as Codon 22 C>T, is reported in the literature in several individuals affected with alpha thalassemia and has been reported in trans to several pathogenic variants (Deshpande 2015, Harteveld 2004, Nainggolan 2010, Nainggolan 2013, HbVar database). The Gly22Gly variant is reported in ClinVar (Variation ID: 15687) and is found on two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in a weakly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic splice donor site. Splicing at this cryptic donor site is predicted to cause a frameshift and premature stop codon (Harteveld 2004). Based on available information, this variant is considered to be likely pathogenic. References: HbVar database entry: https://globin.bx.psu.edu/hbvar/menu.html Deshpande P et al. Characterization of Clinical and Laboratory Profiles of the Deletional a2-Globin Gene Polyadenylation Signal Sequence (AATAAA?>?AATA-?-) in an Indian Population. Hemoglobin. 2015;39(6):415-8. PMID: 26365411 Harteveld CL et al. An alpha-thalassemia phenotype in a Dutch Hindustani, caused by a new point mutation that creates an alternative splice donor site in the first exon of the alpha2-globin gene. Hemoglobin. 2004 Aug;28(3):255-9. PMID: 15481895 Nainggolan IM et al. Hydrops fetalis associated with homozygosity for Hb Adana [alpha59(E8)Gly-->Asp (alpha2)]. Hemoglobin. 2010;34(4):394-401. PMID: 20642338 Nainggolan IM et al. Interaction of Hb adana (HBA2: c.179G>A) with deletional and nondeletional a(+)-thalassemia mutations: diverse hematological and clinical features. Hemoglobin. 2013;37(3):297-305. PMID: 23614625 -

alpha Thalassemia Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Alpha-thalassemia, Dutch type Pathogenic:1

Aug 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	21
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: -2
DS_DL_spliceai		0.47		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63751457; hg19: chr16-222980;