rs34883113

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000558.5(HBA1):c.96-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000082 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.81

Publications

5 publications found

Variant links:

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) 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]

HBA1 Gene-Disease associations (from GenCC):

HBA1-related alpha thalassemia spectrum
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
alpha thalassemia spectrum
Inheritance: SD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
erythrocytosis, familial, 7
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen
unstable hemoglobin disease
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
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
methemoglobinemia, alpha type
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Heinz body anemia
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HBA1 links:

ENSG00000294436 (HGNC:):

ENSG00000294436 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.8, offset of 1, new splice context is: actctgcttctccccgcaAGatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 16-176928-G-A is Pathogenic according to our data. Variant chr16-176928-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 801169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000558.5. 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
	HBA1	NM_000558.5	MANE Select	c.96-1G>A		splice_acceptor intron	N/A	NP_000549.1	P69905

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HBA1	ENST00000320868.9	TSL:1 MANE Select	c.96-1G>A	splice_acceptor intron	N/A	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1	TSL:1	n.231G>A	non_coding_transcript_exon	Exon 1 of 2
HBA1	ENST00000487791.1	TSL:1	n.65-1G>A	splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000602

AC:

AN:

149540

Hom.:

Cov.:

show subpopulations

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:

0.00195

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000171

AC:

AN:

128456

AF XY:

0.000230

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000255

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000821

AC:

AN:

913436

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

468384

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22006

American (AMR)

AF:

0.00

AC:

AN:

35746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21900

East Asian (EAS)

AF:

0.00

AC:

AN:

33808

South Asian (SAS)

AF:

0.00102

AC:

AN:

71642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3132

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

644008

Other (OTH)

AF:

0.0000480

AC:

AN:

41708

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000601

AC:

AN:

149660

Hom.:

Cov.:

AF XY:

0.0000959

AC XY:

AN XY:

73016

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

40400

American (AMR)

AF:

0.00

AC:

AN:

15086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

4984

South Asian (SAS)

AF:

0.00195

AC:

AN:

4610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67470

Other (OTH)

AF:

0.00

AC:

AN:

2038

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000105888), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00

Hom.:

ExAC

AF:

0.0000803

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

alpha Thalassemia (1)

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693798:Methemoglobinemia, alpha type;C4693823:Erythrocytosis, familial, 7 (1)

HBA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Benign

0.91

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

PhyloP100

8.8

GERP RS

3.5

PromoterAI

-0.039

Neutral

(source)

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.81

Position offset: 2

DS_AL_spliceai

1.0

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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