rs63751457

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BP7

The NM_000517.6(HBA2):c.69C>T(p.Gly23=) 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

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -3.95

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 Likely_pathogenic. Variant got 6 ACMG points.

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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).. Strength limited to SUPPORTING due to the PP5.

BP7

Synonymous conserved (PhyloP=-3.95 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.69C>T	p.Gly23=	synonymous_variant	1/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.69C>T	p.Gly23=	synonymous_variant	1/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1 linkuse as main transcript	c.39C>T	p.Gly13=	synonymous_variant	1/2	1
HBA2	ENST00000482565.1 linkuse as main transcript	n.88C>T		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.-2+23C>T		intron_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

53542

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

26986

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

AN:

419174

Hom.:

Cov.:

AF XY:

0.0000363

AC XY:

AN XY:

220470

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 15, 2018

The HBA2 c.69C>T; Gly22Gly variant (rs63751457), 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: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2514 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. 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. Nainggolan IM et al. Hydrops fetalis associated with homozygosity for Hb Adana [alpha59(E8)Gly-->Asp (alpha2)]. Hemoglobin. 2010;34(4):394-401. 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. -

alpha Thalassemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 13, 2021

The variant generates abnormal mRNA splicing and leads to premature termination of alpha-2 globin protein synthesis. It is also associated with alpha(+)-thalassemia (PMID: 15481895 (2004), PMID: 23614625 (2013), PMID: 26365411 (2015)). -

Alpha-thalassemia, Dutch type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

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

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