Genetic Variant HLA-A:c.1046-43C>G (chr6-29945191-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002116.8(HLA-A):c.1046-43C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.0012 ( 0 hom., cov: 10)

Exomes 𝑓: 0.0026 ( 26 hom. )

Consequence

HLA-A
NM_002116.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

11 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-A	NM_002116.8	MANE Select	c.1046-43C>G		intron	N/A	NP_002107.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLA-A	ENST00000376809.10	TSL:6 MANE Select	c.1046-43C>G	intron	N/A	ENSP00000366005.5	P04439-1
HLA-A	ENST00000952344.1		c.1157-43C>G	intron	N/A	ENSP00000622403.1
HLA-A	ENST00000706894.1		c.1046-43C>G	intron	N/A	ENSP00000516610.1	A0A9L9PYF9

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

AN:

76444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000518

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000651

Gnomad ASJ

AF:

0.00567

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.000929

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00167

Gnomad OTH

AF:

0.00397

GnomAD2 exomes

AF:

0.0489

AC:

12163

AN:

248502

AF XY:

0.0515

show subpopulations

Gnomad AFR exome

AF:

0.0311

Gnomad AMR exome

AF:

0.0342

Gnomad ASJ exome

AF:

0.144

Gnomad EAS exome

AF:

0.0316

Gnomad FIN exome

AF:

0.0281

Gnomad NFE exome

AF:

0.0509

Gnomad OTH exome

AF:

0.0486

GnomAD4 exome

AF:

0.00257

AC:

2282

AN:

889274

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

1256

AN XY:

452940

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00213

AC:

AN:

22994

American (AMR)

AF:

0.00408

AC:

139

AN:

34060

Ashkenazi Jewish (ASJ)

AF:

0.00967

AC:

155

AN:

16028

East Asian (EAS)

AF:

0.00522

AC:

131

AN:

25088

South Asian (SAS)

AF:

0.00592

AC:

376

AN:

63488

European-Finnish (FIN)

AF:

0.00102

AC:

AN:

36442

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

3474

European-Non Finnish (NFE)

AF:

0.00195

AC:

1267

AN:

648996

Other (OTH)

AF:

0.00315

AC:

122

AN:

38704

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.324

Heterozygous variant carriers

147

294

441

588

735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00124

AC:

AN:

76502

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

36962

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000517

AC:

AN:

21292

American (AMR)

AF:

0.000650

AC:

AN:

6158

Ashkenazi Jewish (ASJ)

AF:

0.00567

AC:

AN:

1588

East Asian (EAS)

AF:

0.00233

AC:

AN:

2576

South Asian (SAS)

AF:

0.000927

AC:

AN:

2158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

158

European-Non Finnish (NFE)

AF:

0.00167

AC:

AN:

35380

Other (OTH)

AF:

0.00394

AC:

AN:

1016

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0496

Hom.:

214

Asia WGS

AF:

0.0450

AC:

157

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.7

(source)

DANN

Benign

0.47

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over