rs41407250

Positions:

chr16-176765-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PP3_StrongBP6_Very_Strong

The NM_000558.5(HBA1):c.49A>G(p.Lys17Glu) variant causes a missense change. 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. K17M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:5

Conservation

PhyloP100: 4.90

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

BP6

Variant 16-176765-A-G is Benign according to our data. Variant chr16-176765-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 15746.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.49A>G	p.Lys17Glu	missense_variant	1/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBA1	ENST00000320868.9 linkuse as main transcript	c.49A>G	p.Lys17Glu	missense_variant	1/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1 linkuse as main transcript	n.68A>G		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1 linkuse as main transcript	n.18A>G		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000397797.1 linkuse as main transcript	c.-2+3A>G		splice_donor_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150228

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000417

AC:

AN:

1437400

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

713834

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000238

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:

0.00000454

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

150228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73186

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2023	Variant summary: HBA1 c.49A>G (p.Lys17Glu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-06 in 166854 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.49A>G variant (aka Hemoglobin I, Hb I Burlington), is a known hemoglobin variant with altered electrophoretic mobility, and was reported in several asymptomatic heterozygotes, who had no hematological abnormalities (e.g. Saito_1984, Fleming_1978, Arya_2009, Lin_2013). To our knowledge, no homozygous occurrences, or compound heterozygotes with pathogenic HBA1 (or HBA2) variants were reported. The variant was reported in combination with a pathogenic HBB variant, however this individual was only mildly anemic, with a mild hypochromia and microcytosis, which are consistent with the beta-thalassemia carrier state (Arya_2009). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the oxygen equilibrium and kinetic properties of hemoglobin I were indistinguishable from those of the WT (McDonald_1974). Studies also reported that the variant might (slightly) interfere with the measurement of glycosylated hemoglobin (HbA1c) that laboratories should be aware of to avoid mismanagement of individuals carrying this variant (Arya_2009, Zechmeister_2022). The following publications have been ascertained in the context of this evaluation (PMID: 4444049, 6085353, 740406, 19234704, 23806067, 35378091, 5480848). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 09, 2016	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 02, 2022

- -

HEMOGLOBIN I (TEXAS)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN I (SKAMANIA)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN I (BURLINGTON)

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN I

Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN I (PHILADELPHIA)

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

0.35

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.30

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.61

MutationTaster

Benign

0.91

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Vest4

0.75

MutPred

0.88

Loss of MoRF binding (P = 0.0034);

MVP

0.98

ClinPred

0.49

GERP RS

3.3

Varity_R

0.66

gMVP

0.84

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