rs63750751

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_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:7

Conservation

PhyloP100: 3.35

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

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 id is 811900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5 linkuse as main transcript	c.358C>T	p.Pro120Ser	missense_variant	3/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBA1	ENST00000320868.9 linkuse as main transcript	c.358C>T	p.Pro120Ser	missense_variant	3/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1 linkuse as main transcript	n.494C>T		non_coding_transcript_exon_variant	2/2	1
	ENST00000702457.1 linkuse as main transcript	n.151G>A		non_coding_transcript_exon_variant	1/1
HBA1	ENST00000397797.1 linkuse as main transcript	c.262C>T	p.Pro88Ser	missense_variant	3/3	2

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

GnomAD3 exomes

AF:

0.0000566

AC:

AN:

247332

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

134312

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000955

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2022	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 22, 2019	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2022	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) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 20, 2022

- -

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

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

MutationTaster

Benign

1.0

D;D

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

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