chr16-176987-G-C

Position:

chr16-176987-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP3_StrongBP6

The NM_000558.5(HBA1):c.154G>C(p.Gly52Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000675 in 148,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G52D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 31)

Exomes 𝑓: 9.0e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1O:1

Conservation

PhyloP100: 0.759

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

BP6

Variant 16-176987-G-C is Benign according to our data. Variant chr16-176987-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15806.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5 linkuse as main transcript	c.154G>C	p.Gly52Arg	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.154G>C	p.Gly52Arg	missense_variant	2/3	1	NM_000558.5	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1 linkuse as main transcript	n.290G>C		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1 linkuse as main transcript	n.123G>C		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1 linkuse as main transcript	c.58G>C	p.Gly20Arg	missense_variant	2/3	2		ENSP00000380899.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.00000675

AC:

AN:

148128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000252

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:

9.00e-7

AC:

AN:

1111612

Hom.:

Cov.:

AF XY:

0.00000178

AC XY:

AN XY:

561230

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000675

AC:

AN:

148128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72144

show subpopulations

Gnomad4 AFR

AF:

0.0000252

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2022	- -

HEMOGLOBIN RUSS

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

0.0019

Eigen_PC

Benign

-0.032

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.73

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.088

T;T

Vest4

0.69

MutPred

0.96

Gain of solvent accessibility (P = 0.019);.;

MVP

1.0

ClinPred

0.99

GERP RS

3.3

Varity_R

0.90

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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