Genetic Variant HLA-DRB5:c.764-2A>G (chr6-32518079-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PVS1_ModerateBP6_Moderate

The NM_002125.4(HLA-DRB5):c.764-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00025 ( 1 hom., cov: 1)

Exomes 𝑓: 0.000036 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

HLA-DRB5
NM_002125.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.16

Publications

6 publications found

Variant links:

Genes affected

HLA-DRB5 (HGNC:4953): (major histocompatibility complex, class II, DR beta 5) HLA-DRB5 belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DRA) and a beta (DRB) chain, both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa and its gene contains 6 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. There are multiple pseudogenes of this gene. [provided by RefSeq, Feb 2020]

HLA-DRB5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029962547 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.1, offset of 24, new splice context is: ctctggacttcacccaacAGgta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 6-32518079-T-C is Benign according to our data. Variant chr6-32518079-T-C is described in ClinVar as Benign. ClinVar VariationId is 252598.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002125.4. 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-DRB5	NM_002125.4	MANE Select	c.764-2A>G		splice_acceptor intron	N/A	NP_002116.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLA-DRB5	ENST00000374975.4	TSL:6 MANE Select	c.764-2A>G	splice_acceptor intron	N/A	ENSP00000364114.3	Q30154
HLA-DRB5	ENST00000943826.1		c.764-327A>G	intron	N/A	ENSP00000613885.1
HLA-DRB5	ENST00000943827.1		c.737-2A>G	splice_acceptor intron	N/A	ENSP00000613886.1

Frequencies

GnomAD3 genomes

AF:

0.000254

AC:

AN:

39418

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000333

Gnomad ASJ

AF:

0.00187

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000410

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000212

Gnomad OTH

AF:

0.00227

GnomAD2 exomes

AF:

0.000950

AC:

AN:

71566

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.000222

Gnomad AMR exome

AF:

0.000288

Gnomad ASJ exome

AF:

0.00117

Gnomad EAS exome

AF:

0.000191

Gnomad FIN exome

AF:

0.00100

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000364

AC:

AN:

412464

Hom.:

Cov.:

AF XY:

0.0000478

AC XY:

AN XY:

209056

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

9702

American (AMR)

AF:

0.00

AC:

AN:

8922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4264

East Asian (EAS)

AF:

0.00

AC:

AN:

12428

South Asian (SAS)

AF:

0.00

AC:

AN:

32184

European-Finnish (FIN)

AF:

0.000457

AC:

AN:

15308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1366

European-Non Finnish (NFE)

AF:

0.0000258

AC:

AN:

310360

Other (OTH)

AF:

0.00

AC:

AN:

17930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00632609), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.339

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000254

AC:

AN:

39438

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

AN XY:

19264

show subpopulations

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

African (AFR)

AF:

0.000185

AC:

AN:

10798

American (AMR)

AF:

0.000332

AC:

AN:

3010

Ashkenazi Jewish (ASJ)

AF:

0.00187

AC:

AN:

534

East Asian (EAS)

AF:

0.00

AC:

AN:

1434

South Asian (SAS)

AF:

0.00

AC:

AN:

1710

European-Finnish (FIN)

AF:

0.000410

AC:

AN:

2440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000212

AC:

AN:

18850

Other (OTH)

AF:

0.00219

AC:

AN:

456

⚠️ 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: 0.244

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:

0.0388

Hom.:

ExAC

AF:

0.00472

AC:

342

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

(source)

DANN

Benign

0.95

Eigen

Uncertain

0.50

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.24

PhyloP100

2.2

GERP RS

4.7

Mutation Taster

=22/78

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.98

Position offset: -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