16-177059-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP3_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. D76A) has been classified as Likely benign.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 15834.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.226G>T	p.Asp76Tyr	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBA1	ENST00000320868.9 link	c.226G>T	p.Asp76Tyr	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1 link	n.362G>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA1	ENST00000487791.1 link	n.195G>T		non_coding_transcript_exon_variant	Exon 2 of 2	1
HBA1	ENST00000397797.1 link	c.130G>T	p.Asp44Tyr	missense_variant	Exon 2 of 3	2		ENSP00000380899.1	G3V1N2

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000399

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000950

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150394

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73284

show subpopulations

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:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Winnipeg variant (HBA1: c.226G>T; p.Asp76Tyr, also known as Asp75Tyr when numbered from the mature protein, rs33977363, HbVar ID: 113) is reported in the literature in multiple individuals with no clinical symptoms and does not contribute to the clinical phenotype when found with the 3.7kb alpha globin deletion (Nakatsuji 1983, Moradkhani 2009, HbVar database and references therein). This variant is reported in ClinVar (Variation ID: 15834) but is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.751), though functional properties of Hb Winnipeg are reported as normal and stable (Nakatsuji 1983, Moradkhani 2009, HbVar database and references therein). Based on available information, this variant is considered to be likely benign. REFERENCES Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Moradkhani K et al. Mutations in the paralogous human alpha-globin genes yielding identical hemoglobin variants. Ann Hematol. 2009 Jun;88(6):535-43. PMID: 18923834. Nakatsuji T et al. Hb Winnipeg or alpha 2 75(EF4) Asp leads to Tyr beta 2 in a large Caucasian family living in Georgia, USA. Hemoglobin. 1983;7(1):105-10. PMID: 6841125. -

Feb 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA1 c.226G>T (p.Asp76Tyr) variant (also known as Hb Winnipeg) has been described to have normal stability and oxygen affinity (PMID: 6841125 (1983)). Individuals who are heterozygous for this variant have a normal clinical presentation (PMIDs: 6841125 (1983), 4728965 (1973)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant. -

HEMOGLOBIN WINNIPEG

Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.69

T;T

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.71

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.88

MutPred

0.97

Loss of disorder (P = 0.0205);.;

MVP

1.0

ClinPred

1.0

GERP RS

2.3

Varity_R

0.97

gMVP

0.94

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