rs558457816

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000517.6(HBA2):c.95+27C>T variant causes a intron 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 benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 0 hom., cov: 4)

Exomes 𝑓: 0.0081 ( 64 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.782

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

alpha thalassemia spectrum
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
erythrocytosis, familial, 7
Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hemoglobin M disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hb Bart's hydrops fetalis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin H disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Heinz body anemia
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
methemoglobinemia, alpha type
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
unstable hemoglobin disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

HBA2 links:

ENSG00000294455 (HGNC:):

ENSG00000294455 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000517.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 16-173034-C-T is Benign according to our data. Variant chr16-173034-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00812 (3751/461772) while in subpopulation NFE AF = 0.0105 (2867/273496). AF 95% confidence interval is 0.0102. There are 64 homozygotes in GnomAdExome4. There are 1857 alleles in the male GnomAdExome4 subpopulation. Median coverage is 2. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 64 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.95+27C>T		intron	N/A	NP_000508.1	D1MGQ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HBA2	ENST00000251595.11	TSL:1 MANE Select	c.95+27C>T	intron	N/A	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1	TSL:1	c.62+27C>T	intron	N/A	ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1	TSL:1	n.141C>T	non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00474

AC:

AN:

18128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00115

Gnomad AMI

AF:

0.0139

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.00398

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00213

Gnomad FIN

AF:

0.00200

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00705

Gnomad OTH

AF:

0.00327

GnomAD2 exomes

AF:

0.00696

AC:

427

AN:

61338

AF XY:

0.00673

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00774

Gnomad ASJ exome

AF:

0.00469

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00238

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.00812

AC:

3751

AN:

461772

Hom.:

Cov.:

AF XY:

0.00761

AC XY:

1857

AN XY:

243904

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

11878

American (AMR)

AF:

0.00678

AC:

168

AN:

24782

Ashkenazi Jewish (ASJ)

AF:

0.00845

AC:

125

AN:

14790

East Asian (EAS)

AF:

0.00

AC:

AN:

30956

South Asian (SAS)

AF:

0.00207

AC:

100

AN:

48322

European-Finnish (FIN)

AF:

0.00652

AC:

192

AN:

29438

Middle Eastern (MID)

AF:

0.00357

AC:

AN:

1960

European-Non Finnish (NFE)

AF:

0.0105

AC:

2867

AN:

273496

Other (OTH)

AF:

0.0101

AC:

265

AN:

26150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

218

436

655

873

1091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00470

AC:

AN:

18098

Hom.:

Cov.:

AF XY:

0.00535

AC XY:

AN XY:

8040

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

2616

American (AMR)

AF:

0.00522

AC:

AN:

2298

Ashkenazi Jewish (ASJ)

AF:

0.00398

AC:

AN:

502

East Asian (EAS)

AF:

0.00

AC:

AN:

1324

South Asian (SAS)

AF:

0.00216

AC:

AN:

926

European-Finnish (FIN)

AF:

0.00200

AC:

AN:

1000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

124

European-Non Finnish (NFE)

AF:

0.00695

AC:

AN:

8922

Other (OTH)

AF:

0.00318

AC:

AN:

314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00583

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

6.9

(source)

DANN

Benign

0.84

PhyloP100

0.78

PromoterAI

-0.077

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over