NM_000558.5:c.154G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP6_Moderate

The NM_000558.5(HBA1):c.154G>A(p.Gly52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 148,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G52R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00051 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 0.759

Publications

6 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: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 29 uncertain in NM_000558.5

BP6

Variant 16-176987-G-A is Benign according to our data. Variant chr16-176987-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 15889.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.154G>A	p.Gly52Ser	missense_variant	Exon 2 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.154G>A	p.Gly52Ser	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5		P69905

Frequencies

GnomAD3 genomes

AF:

0.000324

AC:

AN:

148126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000503

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000673

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:

0.000671

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000280

AC:

AN:

139410

AF XY:

0.000315

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.0000403

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000650

Gnomad OTH exome

AF:

0.000239

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000507

AC:

564

AN:

1111556

Hom.:

Cov.:

AF XY:

0.000453

AC XY:

254

AN XY:

561198

show subpopulations

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

African (AFR)

AF:

0.000267

AC:

AN:

26252

American (AMR)

AF:

0.0000534

AC:

AN:

37456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23524

East Asian (EAS)

AF:

0.00

AC:

AN:

35316

South Asian (SAS)

AF:

0.00

AC:

AN:

76772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3498

European-Non Finnish (NFE)

AF:

0.000660

AC:

544

AN:

824318

Other (OTH)

AF:

0.000227

AC:

AN:

48546

⚠️ 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: 0.372

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000324

AC:

AN:

148126

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

72142

show subpopulations

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

African (AFR)

AF:

0.0000503

AC:

AN:

39740

American (AMR)

AF:

0.0000673

AC:

AN:

14856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

5048

South Asian (SAS)

AF:

0.00

AC:

AN:

4480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000671

AC:

AN:

67112

Other (OTH)

AF:

0.00

AC:

AN:

1972

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.371

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:

0.0000791

Hom.:

ExAC

AF:

0.000106

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HBA1-related disorder

Benign:1

Feb 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Jun 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb Riccarton variant (HBA1: c.154G>A; p.Gly52Ser, also known as Gly51Ser when numbered from the mature protein, rs33960522, HbVar ID: 1233) is reported in the literature in the heterozygous state in multiple asymptomatic individuals (see HbVar and references therein). This variant was also observed in one individual with alpha (+) thalassemia on the same allele as splice acceptor site variant c.301-2A>T (Scheps 2012). However, the phenotype of this variant in the presence of other alpha globin variants is unknown. This variant is also reported in ClinVar (Variation ID: 15889) and is found in the non- Finnish European population with an allele frequency of 0.06% (44/70302 alleles) in the Genome Aggregation Database. The glycine at codon 52 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.772). Based on available information, the p.Gly52Ser variant is considered to be likely benign. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Scheps KG et al. Identification of a new HBA1 gene mutation (HBA1:c.301-2A>T) in cis with Hb Riccarton (HBA1:c.154G>A) (alpha51(CE9)Gly>Ser). Hemoglobin. 2012;36(5):504-7. PMID: 22738642 -

HEMOGLOBIN RICCARTON

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

Benign

0.16

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

0.0019

Eigen_PC

Benign

-0.032

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.68

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Uncertain

0.68

PhyloP100

0.76

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.052

T;T

Vest4

0.43

MVP

1.0

ClinPred

0.67

GERP RS

3.3

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.71

gMVP

0.81

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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