rs281864849

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_ModerateBP6_Very_Strong

The NM_000517.6(HBA2):c.193G>A(p.Asp65Asn) variant causes a missense 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 benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D65Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.727

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_benign. Variant got -6 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

BP6

Variant 16-173222-G-A is Benign according to our data. Variant chr16-173222-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 994321.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.193G>A	p.Asp65Asn	missense_variant	2/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.193G>A	p.Asp65Asn	missense_variant	2/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000484216.1 linkuse as main transcript	c.163G>A	p.Asp55Asn	missense_variant	2/2	1		ENSP00000495899
HBA2	ENST00000482565.1 linkuse as main transcript	n.329G>A		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.97G>A	p.Asp33Asn	missense_variant	2/3	2		ENSP00000380908

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

124330

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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:

0.00000755

AC:

AN:

132396

Hom.:

AF XY:

0.00

AC XY:

AN XY:

71564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000944

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

AF:

0.00000174

AC:

AN:

1148970

Hom.:

Cov.:

AF XY:

0.00000173

AC XY:

AN XY:

576544

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000288

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000115

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

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

AF:

0.00

AC:

AN:

124330

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

59750

Gnomad4 AFR

AF:

0.00

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

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 23, 2024

Variant summary: HBA2 c.193G>A (p.Asp65Asn) results in a conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 155296 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.193G>A has been reported in the literature in the heterozygous state in asymptomatic individuals and in the compound heterozyougs state in at least one indiviudal with symptoms consistent with being an alpha thalassemia carrier (e.g. Cantan_2016, Lin_2009, DiGeorge_2014, Landin_1994, Manca_1994). In addition, this variant has been reported in the heterozygous state in at least one individual with mild microcytic anemia who also had homozygous beta thalassemia variants (e.g. Baine_1979). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is also known as Hb G-Waimanalo and Hb Aida. The following publications have been ascertained in the context of this evaluation (PMID: 500373, 27020723, 24594475, 8195011, 19010698, 21231928, 8195008). ClinVar contains an entry for this variant (Variation ID: 994321). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0087

.;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.041

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

-0.26

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.054

T;D

Sift4G

Benign

0.66

T;T

Vest4

0.56

MutPred

0.91

Gain of MoRF binding (P = 0.0491);.;

MVP

1.0

MPC

1.3

ClinPred

0.059

GERP RS

4.2

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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