chr16-177040-C-G

Position:

chr16-177040-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2PP3BP6_Very_Strong

The NM_000558.5(HBA1):c.207C>G(p.Asn69Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,466,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -7.23

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:

HBA1 (HGNC:):

HBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.757

BP6

Variant 16-177040-C-G is Benign according to our data. Variant chr16-177040-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 439095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5 linkuse as main transcript	c.207C>G	p.Asn69Lys	missense_variant	2/3	ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBA1	ENST00000320868.9 linkuse as main transcript	c.207C>G	p.Asn69Lys	missense_variant	2/3	1	NM_000558.5	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1 linkuse as main transcript	n.343C>G		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1 linkuse as main transcript	n.176C>G		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1 linkuse as main transcript	c.111C>G	p.Asn37Lys	missense_variant	2/3	2		ENSP00000380899.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.0000933

AC:

AN:

150128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

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

GnomAD3 exomes

AF:

0.0000293

AC:

AN:

136744

Hom.:

AF XY:

0.0000269

AC XY:

AN XY:

74274

show subpopulations

Gnomad AFR exome

AF:

0.000567

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000608

AC:

AN:

1316688

Hom.:

Cov.:

AF XY:

0.00000612

AC XY:

AN XY:

654116

show subpopulations

Gnomad4 AFR exome

AF:

0.000264

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000932

AC:

AN:

150242

Hom.:

Cov.:

AF XY:

0.0000682

AC XY:

AN XY:

73268

show subpopulations

Gnomad4 AFR

AF:

0.000319

Gnomad4 AMR

AF:

0.0000663

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

Bravo

AF:

0.0000756

ExAC

AF:

0.00000967

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.21

CADD

Benign

0.035

DANN

Benign

0.59

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.69

T;T

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.51

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.89

N;N

REVEL

Uncertain

0.38

Sift

Benign

1.0

T;T

Sift4G

Benign

0.56

T;T

Vest4

0.57

MutPred

0.95

Gain of ubiquitination at N69 (P = 0.0211);.;

MVP

0.98

ClinPred

0.75

GERP RS

-8.6

Varity_R

0.57

gMVP

0.80

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