dbSNP rs1061235: HLA-A:c.*66A>T (chr6-29945521-A-T) – 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.*66A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.022 ( 3 hom., cov: 24)

Exomes 𝑓: 0.0054 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

HLA-A
NM_002116.8 3_prime_UTR

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: -0.347

Publications

46 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8 link	c.*66A>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000376809.10	NP_002107.3
LOC124901298	XR_007059541.1 link	n.73T>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10 link	c.*66A>T		3_prime_UTR_variant	Exon 8 of 8	6	NM_002116.8	ENSP00000366005.5

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3195

AN:

142960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0284

Gnomad AMI

AF:

0.00444

Gnomad AMR

AF:

0.0281

Gnomad ASJ

AF:

0.0218

Gnomad EAS

AF:

0.0415

Gnomad SAS

AF:

0.0542

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0428

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.0242

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00536

AC:

4410

AN:

822874

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

2478

AN XY:

428224

show subpopulations

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

African (AFR)

AF:

0.00870

AC:

172

AN:

19762

American (AMR)

AF:

0.00916

AC:

299

AN:

32628

Ashkenazi Jewish (ASJ)

AF:

0.00777

AC:

141

AN:

18152

East Asian (EAS)

AF:

0.0272

AC:

880

AN:

32370

South Asian (SAS)

AF:

0.0145

AC:

907

AN:

62420

European-Finnish (FIN)

AF:

0.00631

AC:

253

AN:

40108

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

4288

European-Non Finnish (NFE)

AF:

0.00259

AC:

1489

AN:

574648

Other (OTH)

AF:

0.00579

AC:

223

AN:

38498

⚠️ 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: 0.294

Heterozygous variant carriers

365

729

1094

1458

1823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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: AS_VQSR

AF:

0.0224

AC:

3210

AN:

143072

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1639

AN XY:

69568

show subpopulations

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

African (AFR)

AF:

0.0285

AC:

1080

AN:

37904

American (AMR)

AF:

0.0285

AC:

401

AN:

14086

Ashkenazi Jewish (ASJ)

AF:

0.0218

AC:

AN:

3306

East Asian (EAS)

AF:

0.0414

AC:

190

AN:

4588

South Asian (SAS)

AF:

0.0550

AC:

232

AN:

4218

European-Finnish (FIN)

AF:

0.0261

AC:

265

AN:

10134

Middle Eastern (MID)

AF:

0.0426

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0138

AC:

907

AN:

65686

Other (OTH)

AF:

0.0239

AC:

AN:

1968

⚠️ 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: 0.313

Heterozygous variant carriers

211

422

632

843

1054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0315

Hom.:

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Carbamazepine hypersensitivity

Other:1

Jul 01, 2013

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.4

(source)

DANN

Benign

0.60

PhyloP100

-0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over