NM_000558.5:c.226G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_StrongBP6

The NM_000558.5(HBA1):c.226G>T(p.Asp76Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000861 in 1,510,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1O:1

Conservation

PhyloP100: -0.0490

Publications

11 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: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

BP6

Variant 16-177059-G-T is Benign according to our data. Variant chr16-177059-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15834.

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.226G>T	p.Asp76Tyr	missense	Exon 2 of 3	NP_000549.1	P69905

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HBA1	ENST00000320868.9	TSL:1 MANE Select	c.226G>T	p.Asp76Tyr	missense	Exon 2 of 3	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1	TSL:1	n.362G>T		non_coding_transcript_exon	Exon 1 of 2
HBA1	ENST00000487791.1	TSL:1	n.195G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150394

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000882

AC:

AN:

1359774

Hom.:

Cov.:

AF XY:

0.00000890

AC XY:

AN XY:

674410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31292

American (AMR)

AF:

0.00

AC:

AN:

37274

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25044

East Asian (EAS)

AF:

0.00

AC:

AN:

36494

South Asian (SAS)

AF:

0.00

AC:

AN:

80504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4030

European-Non Finnish (NFE)

AF:

0.00000950

AC:

AN:

1052708

Other (OTH)

AF:

0.0000175

AC:

AN:

57084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

AF:

0.00000665

AC:

AN:

150394

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40952

American (AMR)

AF:

0.00

AC:

AN:

15094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67278

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

HEMOGLOBIN WINNIPEG (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.37

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.71

PhyloP100

-0.049

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.88

MutPred

0.97

Loss of disorder (P = 0.0205)

MVP

1.0

ClinPred

1.0

GERP RS

2.3

PromoterAI

-0.048

Neutral

(source)

Varity_R

0.97

gMVP

0.94

Mutation Taster

=14/86

disease causing

(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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over