rs63750751

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000558.5(HBA1):c.358C>T(p.Pro120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,180 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 1 hom. )

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.35

Publications

10 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):

alpha thalassemia spectrum
Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
erythrocytosis, familial, 7
Inheritance: AD Classification: STRONG Submitted by: 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
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 14 ACMG points.

PM1

In a helix (size 18) in uniprot entity HBA_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000558.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 16-177340-C-T is Pathogenic according to our data. Variant chr16-177340-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 811900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.358C>T	p.Pro120Ser	missense_variant	Exon 3 of 3	ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9 link	c.358C>T	p.Pro120Ser	missense_variant	Exon 3 of 3	1	NM_000558.5	ENSP00000322421.5		P69905

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000294

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.0000566

AC:

AN:

247332

AF XY:

0.0000447

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000628

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460978

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.000157

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53082

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1111742

Other (OTH)

AF:

0.000133

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000102

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Pathogenic:3

Jun 22, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HBA1 c.358C>T (p.Pro120Ser) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 247332 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HBA1 causing Alpha Thalassemia (5.7e-05 vs 0.0056), allowing no conclusion about variant significance. c.358C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Alpha Thalassemia (e.g. Giordano_2007, Zanella-Cleon_2008, Joly_2014). These data indicate that the variant is very likely to be associated with disease. In vitro binding assays indicate that while the variant protein is capable of forming dimers, it does not interact with alpha hemoglobin stabilizing proteins or beta subunits, leading to destabilization and increased proteolytic degredation (Yu_2009). Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 20, 2019

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Nov 11, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Also reported as Hb Groene Hart [119(H2)Pro>Ser (1); HBA1: c.358C>T]; Observed in the heterozygous state in alpha thalassemia carriers or patients with mild phenotypes (Giambona A et al., 2008; Cardiero G et al., 2020); Published functional studies demonstrate a damaging effect on the interaction with alpha hemoglobin stabilizing protein and the beta subunit (Yu X et al., 2009; Wajcman H et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21950764, 12403490, 25130136, 18603555, 23806011, 17486500, 19349619, 24111644, 32751969, 31553106, 26485748) -

Aug 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA1 c.358C>T; p.Pro120Ser variant (Hb Groene Hart, also known as Pro119Ser when numbered from the mature protein, rs63750751, HbVar ID: 1123) has been described in the compound heterozygous or homozygous state in individuals affected with alpha thalassemia, and in the heterozygous state in individuals with microcytosis and hypochromia (see link to HbVar, Giordano 2007, Harteveld 2002, Joly 2014, Yu 2009, Zanella-Cleon 2008). This variant is found in the general population with an overall allele frequency of 0.0057% (16/278694 alleles) in the Genome Aggregation Database. Functional studies of the variant protein demonstrate impaired binding to alpha hemoglobin stabilizing protein and beta globin, leading to destabilization and increased proteolytic degradation (Yu 2009). Based on available information, this variant is considered pathogenic. REFERENCES Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Giordano P et al. The first case of Hb Groene Hart (alpha119(H2)Pro-->Ser, CCT-->TCT (alpha1)) homozygosity confirms that a thalassemia phenotype is associated with this abnormal hemoglobin variant. Hemoglobin. 2007;31(2):179-82. PMID: 17486500. Harteveld C et al. Hb Groene Hart: a new Pro-->Ser amino acid substitution at position 119 of the alpha1-globin chain is associated with a mild alpha-thalassemia phenotype. Hemoglobin. 2002 Aug;26(3):255-60. PMID: 12403490. Joly P et al. Description of the phenotypes of 63 heterozygous, homozygous and compound heterozygous patients carrying the Hb Groene Hart (alpha119(H2)Pro->Ser; HBA1: c.358C>T) variant. Hemoglobin. 2014;38(1):64-6. PMID: 24111644. Yu X et al. Analysis of human alpha globin gene mutations that impair binding to the alpha hemoglobin stabilizing protein. Blood. 2009 Jun 4;113(23):5961-9. PMID: 19349619. Zanella-Cleon I et al. Detection of a thalassemic alpha-chain variant (Hemoglobin Groene Hart) by reversed-phase liquid chromatography. Clin Chem. 2008 Jun;54(6):1053-9. PMID: 18420733. -

Feb 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA1 c.358C>T (p.Pro120Ser) variant has been reported in the heterozygous and compound heterozygous state in individuals with mild alpha-thalassemia phenotype (PMIDs: 26485748 (2016), 24111644 (2014), 16370486 (2005), 12403490 (2002)). Individuals who are homozygous for this variant present with microcytic hypochromic anemia (PMIDs: 24111644 (2014), 17486500 (2007)). Experimental studies indicate this variant disrupts binding of the alpha globin chains to the AHSP (alpha hemoglobin stabilizing protein) and results in an unstable hemoglobin complex (PMIDs: 21950764 (2011), 19349619 (2009), 17052927(2006)). Based on the available information, this variant is classified as pathogenic. -

HBA1-related disorder

Pathogenic:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HBA1 c.358C>T variant is predicted to result in the amino acid substitution p.Pro120Ser. This variant is also referred to as p.Pro119Ser or Hb Groene Hart. This variant has been reported in the heterozygous state in a father and son with microcytic hypochromic anemia (Harteveld et al. 2002. PubMed ID: 12403490) and in the homozygous state and in the heterozygous state along with an -α3.7 deletion in patients with alpha thalassemia (Joly et al. 2013. PubMed ID: 24111644; Giordano et al. 2007. PubMed ID: 174865000). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Jan 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.72

D;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.39

PhyloP100

3.3

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.017

D;D

Vest4

0.69

MutPred

0.88

Loss of phosphorylation at T119 (P = 0.1015);.;

MVP

1.0

ClinPred

0.53

GERP RS

0.94

Varity_R

0.90

gMVP

0.94

Mutation Taster

=2/98

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over