rs2230954

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002116.8(HLA-A):c.41C>A(p.Ser14*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000998 in 1,002,374 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.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 17)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.59

Publications

23 publications found

Variant links:

Genes affected

HLA-A (HGNC:4931): (major histocompatibility complex, class I, A) HLA-A belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen so that they can be recognized by cytotoxic T cells. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. More than 6000 HLA-A alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]

HLA-A links:

ENSG00000227766 (HGNC:):

ENSG00000227766 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002116.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	NM_002116.8	MANE Select	c.41C>A	p.Ser14*	stop_gained	Exon 1 of 8	NP_002107.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.41C>A	p.Ser14*	stop_gained	Exon 1 of 8	ENSP00000366005.5
HLA-A	ENST00000706894.1		c.41C>A	p.Ser14*	stop_gained	Exon 2 of 8	ENSP00000516610.1
HLA-A	ENST00000376806.9	TSL:6	c.41C>A	p.Ser14*	stop_gained	Exon 1 of 8	ENSP00000366002.5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

104268

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

226232

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.98e-7

AC:

AN:

1002374

Hom.:

Cov.:

AF XY:

0.00000200

AC XY:

AN XY:

499664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23528

American (AMR)

AF:

0.00

AC:

AN:

22088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16356

East Asian (EAS)

AF:

0.00

AC:

AN:

26232

South Asian (SAS)

AF:

0.00

AC:

AN:

62278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3708

European-Non Finnish (NFE)

AF:

0.00000130

AC:

AN:

770140

Other (OTH)

AF:

0.00

AC:

AN:

42616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

104268

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50196

African (AFR)

AF:

0.00

AC:

AN:

29004

American (AMR)

AF:

0.00

AC:

AN:

9276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2380

East Asian (EAS)

AF:

0.00

AC:

AN:

3492

South Asian (SAS)

AF:

0.00

AC:

AN:

3404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

47636

Other (OTH)

AF:

0.00

AC:

AN:

1402

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.010

PhyloP100

-4.6

Vest4

0.63

GERP RS

-1.4

PromoterAI

-0.19

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=164/36

disease causing (fs/PTC)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over