dbSNP rs1050384: HLA-C:p.Pro129Pro (chr6-31271305-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP7

The NM_002117.6(HLA-C):c.387C>G(p.Pro129Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 0.0019 ( 1 hom., cov: 6)

Exomes 𝑓: 0.0073 ( 287 hom. )

Failed GnomAD Quality Control

Consequence

HLA-C
NM_002117.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -6.48

Publications

13 publications found

Variant links:

Genes affected

HLA-C (HGNC:4933): (major histocompatibility complex, class I, C) HLA-C 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 endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, 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. About 6000 HLA-C 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-C links:

ENSG00000298396 (HGNC:):

ENSG00000298396 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.028).

BP7

Synonymous conserved (PhyloP=-6.48 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.387C>G	p.Pro129Pro	synonymous_variant	Exon 3 of 8	ENST00000376228.10	NP_002108.4	P10321-1Q6R739Q95HC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10 link	c.387C>G	p.Pro129Pro	synonymous_variant	Exon 3 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

121

AN:

62276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.00655

Gnomad AMR

AF:

0.00213

Gnomad ASJ

AF:

0.00227

Gnomad EAS

AF:

0.00665

Gnomad SAS

AF:

0.00238

Gnomad FIN

AF:

0.00163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000734

Gnomad OTH

AF:

0.00535

GnomAD2 exomes

AF:

0.141

AC:

31387

AN:

222356

AF XY:

0.138

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.201

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.0743

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00729

AC:

7209

AN:

988374

Hom.:

287

Cov.:

AF XY:

0.00795

AC XY:

3941

AN XY:

495880

show subpopulations

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

African (AFR)

AF:

0.0250

AC:

482

AN:

19316

American (AMR)

AF:

0.0193

AC:

532

AN:

27576

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

391

AN:

14158

East Asian (EAS)

AF:

0.0254

AC:

582

AN:

22876

South Asian (SAS)

AF:

0.0285

AC:

1805

AN:

63224

European-Finnish (FIN)

AF:

0.00371

AC:

117

AN:

31526

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

2998

European-Non Finnish (NFE)

AF:

0.00360

AC:

2763

AN:

766762

Other (OTH)

AF:

0.0124

AC:

497

AN:

39938

⚠️ 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: 0.368

Heterozygous variant carriers

382

764

1147

1529

1911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00193

AC:

120

AN:

62308

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

AN XY:

29720

show subpopulations

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

African (AFR)

AF:

0.00406

AC:

AN:

12818

American (AMR)

AF:

0.00213

AC:

AN:

5628

Ashkenazi Jewish (ASJ)

AF:

0.00227

AC:

AN:

882

East Asian (EAS)

AF:

0.00670

AC:

AN:

1642

South Asian (SAS)

AF:

0.00238

AC:

AN:

1684

European-Finnish (FIN)

AF:

0.00163

AC:

AN:

4300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000734

AC:

AN:

34044

Other (OTH)

AF:

0.00529

AC:

AN:

756

⚠️ 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: 0.286

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.130

Hom.:

Asia WGS

AF:

0.186

AC:

648

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_noAF

Benign

-0.94

CADD

Benign

9.8

(source)

DANN

Benign

0.63

PhyloP100

-6.5

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)

0.030

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