rs63749882

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PP3_ModerateBP6_Moderate

The NM_000558.5(HBA1):c.349G>A(p.Glu117Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 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. E117Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 1 hom. )

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2O:5

Conservation

PhyloP100: 4.82

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

BP6

Variant 16-177331-G-A is Benign according to our data. Variant chr16-177331-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 15793.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5 linkuse as main transcript	c.349G>A	p.Glu117Lys	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.349G>A	p.Glu117Lys	missense_variant	3/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1 linkuse as main transcript	n.485G>A		non_coding_transcript_exon_variant	2/2	1
	ENST00000702457.1 linkuse as main transcript	n.160C>T		non_coding_transcript_exon_variant	1/1
HBA1	ENST00000397797.1 linkuse as main transcript	c.253G>A	p.Glu85Lys	missense_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000811

AC:

AN:

246712

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134042

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000658

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460982

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726774

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:5

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

alpha Thalassemia

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 24, 2022

- -

HEMOGLOBIN O (BUGINESE-X)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN BUGINESE-X

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN O (OLIVIERE)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN OLIVIERE

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN O (INDONESIA)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.38

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.61

T;T

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.30

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.046

D;T

Vest4

0.48

MutPred

0.77

Gain of methylation at E117 (P = 0.0062);.;

MVP

1.0

ClinPred

0.87

GERP RS

3.3

Varity_R

0.48

gMVP

0.75

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