dbSNP rs9260105: HLA-A:c.-281-68G>T (chr6-29941898-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000396634.5(HLA-A):c.-281-68G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 169,394 control chromosomes in the GnomAD database, including 200 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.045 ( 177 hom., cov: 35)

Exomes 𝑓: 0.035 ( 23 hom. )

Consequence

HLA-A
ENST00000396634.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0680

Publications

1 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:

POLR1HASP (HGNC:):

POLR1HASP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124901298	XR_007059541.1 link	n.813+2883C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
HLA-A	ENST00000396634.5 link	c.-281-68G>T	intron_variant	Intron 1 of 9	6	ENSP00000379873.1	P04439-1
POLR1HASP	ENST00000849679.1 link	n.66-13352C>A	intron_variant	Intron 1 of 5
POLR1HASP	ENST00000849682.1 link	n.751-13352C>A	intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0451

AC:

6854

AN:

152118

Hom.:

176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0707

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.00558

Gnomad SAS

AF:

0.0352

Gnomad FIN

AF:

0.0411

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0376

Gnomad OTH

AF:

0.0402

GnomAD4 exome

AF:

0.0346

AC:

594

AN:

17158

Hom.:

AF XY:

0.0375

AC XY:

393

AN XY:

10486

show subpopulations

African (AFR)

AF:

0.0685

AC:

AN:

292

American (AMR)

AF:

0.0183

AC:

AN:

654

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

418

East Asian (EAS)

AF:

0.00185

AC:

AN:

540

South Asian (SAS)

AF:

0.0346

AC:

178

AN:

5142

European-Finnish (FIN)

AF:

0.0277

AC:

AN:

542

Middle Eastern (MID)

AF:

0.0556

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0388

AC:

331

AN:

8534

Other (OTH)

AF:

0.0264

AC:

AN:

946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

104

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

AF:

0.0451

AC:

6866

AN:

152236

Hom.:

177

Cov.:

AF XY:

0.0452

AC XY:

3361

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0707

AC:

2937

AN:

41528

American (AMR)

AF:

0.0325

AC:

497

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00559

AC:

AN:

5188

South Asian (SAS)

AF:

0.0352

AC:

170

AN:

4830

European-Finnish (FIN)

AF:

0.0411

AC:

435

AN:

10594

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0376

AC:

2556

AN:

68012

Other (OTH)

AF:

0.0402

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

290

580

871

1161

1451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0430

Hom.:

Bravo

AF:

0.0464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

6.2

(source)

DANN

Benign

0.74

PhyloP100

-0.068

PromoterAI

0.0079

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over