Genetic Variant HBA1:p.Lys17Asn (chr16-176767-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000558.5(HBA1):c.51G>T(p.Lys17Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K17E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.831

Publications

7 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.51G>T	p.Lys17Asn	missense_variant	Exon 1 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9 link	c.51G>T	p.Lys17Asn	missense_variant	Exon 1 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437574

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713892

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32502

American (AMR)

AF:

0.00

AC:

AN:

41990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25760

East Asian (EAS)

AF:

0.00

AC:

AN:

38680

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4400

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100324

Other (OTH)

AF:

0.00

AC:

AN:

59368

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.74

PhyloP100

0.83

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.71

MutPred

0.84

Loss of ubiquitination at K17 (P = 0.0255);

MVP

0.99

ClinPred

0.99

GERP RS

4.4

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.83

gMVP

0.85

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over