Variant 16-172913-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000517.6(HBA2):c.1A>G(p.Met1?) variant causes a start lost change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.29

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PP5

Variant 16-172913-A-G is Pathogenic according to our data. Variant chr16-172913-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 15645.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 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000482565.1 link	n.20A>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806 link	c.-47A>G		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000380908.1	G3V1N2
HBA2	ENST00000484216.1 link	c.-33A>G		upstream_gene_variant		1		ENSP00000495899.1	A0A2R8Y7C0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

268918

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

143308

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Nov 25, 2019

- -

Hemoglobin H disease, nondeletional

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1987

- -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 04, 2020

The variant disrupts the natural start codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

DANN

Uncertain

0.98

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.79

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.97

MutPred

1.0

Loss of MoRF binding (P = 0.0883);

MVP

1.0

ClinPred

0.98

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

gMVP

0.63

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