chr16-173192-C-T

Position:

chr16-173192-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000517.6(HBA2):c.163C>T(p.Gln55*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., cov: 15)

Exomes 𝑓: 0.0000033 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 0.141

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:

HBA2 (HGNC:):

HBA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-173192-C-T is Pathogenic according to our data. Variant chr16-173192-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1330821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.163C>T	p.Gln55*	stop_gained	2/3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 linkuse as main transcript	c.163C>T	p.Gln55*	stop_gained	2/3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1 linkuse as main transcript	c.130C>T	p.Gln44*	stop_gained	2/2	1		ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1 linkuse as main transcript	n.299C>T		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.67C>T	p.Gln23*	stop_gained	2/3	2		ENSP00000380908.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.0000354

AC:

AN:

112862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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:

0.0000153

AC:

AN:

130456

Hom.:

AF XY:

0.0000284

AC XY:

AN XY:

70532

show subpopulations

Gnomad AFR exome

AF:

0.000313

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

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:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000329

AC:

AN:

912156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

467932

show subpopulations

Gnomad4 AFR exome

AF:

0.000160

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000354

AC:

AN:

112862

Hom.:

Cov.:

AF XY:

0.0000556

AC XY:

AN XY:

53936

show subpopulations

Gnomad4 AFR

AF:

0.000186

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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

ExAC

AF:

0.0000104

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 15, 2023	The c.163C>T (p.Gln55*) nonsense variant causes the premature termination of HBA2 protein synthesis and is associated with haemolytic anemia (ITHANET (http://www.ithanet.eu/)). In the published literature, this variant has been reported in one affected individual with mild microcytosis and hypochromia (PMID: 19205977 (2009)). Based on this information, the variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 02, 2021	The HBA2 c.163C>T; p.Gln55Ter, variant (also known as Gln54Ter when numbered from the mature protein, rs281864840) been reported in the heterozygous state in an individual with microcytosis and hypochromia and normal Hb pattern (Eng 2009). This variant is found in the African population with an allele frequency of 0.03% (2/6384 alleles, including 1 homozygote) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Eng B et al. Alpha+-thalassemia trait caused by a nonsense mutation in the alpha2-globin gene: codon 54 (CAG>TAG). Hemoglobin. 2009;33(1):72-4. PMID: 19205977. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.32

Eigen_PC

Benign

-0.013

FATHMM_MKL

Benign

0.31

Vest4

0.71

GERP RS

3.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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