6-32518079-T-C

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

1
6
Splicing: ADA: 1.000
2

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]

Genome browser will be placed here

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 id is 252598.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HLA-DRB5NM_002125.4 linkc.764-2A>G splice_acceptor_variant, intron_variant Intron 4 of 5 ENST00000374975.4 NP_002116.2 Q30154A0A2Z4LKS3
HLA-DRB5XM_011514562.3 linkc.764-2A>G splice_acceptor_variant, intron_variant Intron 4 of 5 XP_011512864.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HLA-DRB5ENST00000374975.4 linkc.764-2A>G splice_acceptor_variant, intron_variant Intron 4 of 5 6 NM_002125.4 ENSP00000364114.3 Q30154
HLA-DRB5ENST00000714490.1 linkc.674-2A>G splice_acceptor_variant, intron_variant Intron 4 of 5 ENSP00000519744.1

Frequencies

GnomAD3 genomes
AF:
0.000254
AC:
10
AN:
39418
Hom.:
1
Cov.:
1
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:
68
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:
15
AN:
412464
Hom.:
4
Cov.:
0
AF XY:
0.0000478
AC XY:
10
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:
0
AN:
9702
American (AMR)
AF:
0.00
AC:
0
AN:
8922
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
4264
East Asian (EAS)
AF:
0.00
AC:
0
AN:
12428
South Asian (SAS)
AF:
0.00
AC:
0
AN:
32184
European-Finnish (FIN)
AF:
0.000457
AC:
7
AN:
15308
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1366
European-Non Finnish (NFE)
AF:
0.0000258
AC:
8
AN:
310360
Other (OTH)
AF:
0.00
AC:
0
AN:
17930
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006326), 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
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Hom
Variant carriers
0
2
4
6
8
10
<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:
10
AN:
39438
Hom.:
1
Cov.:
1
AF XY:
0.000260
AC XY:
5
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:
2
AN:
10798
American (AMR)
AF:
0.000332
AC:
1
AN:
3010
Ashkenazi Jewish (ASJ)
AF:
0.00187
AC:
1
AN:
534
East Asian (EAS)
AF:
0.00
AC:
0
AN:
1434
South Asian (SAS)
AF:
0.00
AC:
0
AN:
1710
European-Finnish (FIN)
AF:
0.000410
AC:
1
AN:
2440
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
54
European-Non Finnish (NFE)
AF:
0.000212
AC:
4
AN:
18850
Other (OTH)
AF:
0.00219
AC:
1
AN:
456
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), 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
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<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.:
1
ExAC
AF:
0.00472
AC:
342

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Oct 13, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Uncertain
24
DANN
Benign
0.95
Eigen
Uncertain
0.50
Eigen_PC
Benign
0.21
FATHMM_MKL
Benign
0.24
N
PhyloP100
2.2
GERP RS
4.7
Mutation Taster
=22/78
polymorphism (auto)

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

Other links and lift over

dbSNP: rs201699945; hg19: chr6-32485856; COSMIC: COSV66615747; API