6-32518079-T-C
Variant names:
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
NM_002125.4 splice_acceptor, intron
Scores
1
6
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 2.16
Publications
6 publications found
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-DRB5 | NM_002125.4 | c.764-2A>G | splice_acceptor_variant, intron_variant | Intron 4 of 5 | ENST00000374975.4 | NP_002116.2 | ||
HLA-DRB5 | XM_011514562.3 | c.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-DRB5 | ENST00000374975.4 | c.764-2A>G | splice_acceptor_variant, intron_variant | Intron 4 of 5 | 6 | NM_002125.4 | ENSP00000364114.3 | |||
HLA-DRB5 | ENST00000714490.1 | c.674-2A>G | splice_acceptor_variant, intron_variant | Intron 4 of 5 | ENSP00000519744.1 |
Frequencies
GnomAD3 genomes AF: 0.000254 AC: 10AN: 39418Hom.: 1 Cov.: 1 show subpopulations
GnomAD3 genomes
AF:
AC:
10
AN:
39418
Hom.:
Cov.:
1
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.000950 AC: 68AN: 71566 AF XY: 0.00119 show subpopulations
GnomAD2 exomes
AF:
AC:
68
AN:
71566
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000364 AC: 15AN: 412464Hom.: 4 Cov.: 0 AF XY: 0.0000478 AC XY: 10AN XY: 209056 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
15
AN:
412464
Hom.:
Cov.:
0
AF XY:
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:
AC:
0
AN:
9702
American (AMR)
AF:
AC:
0
AN:
8922
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
4264
East Asian (EAS)
AF:
AC:
0
AN:
12428
South Asian (SAS)
AF:
AC:
0
AN:
32184
European-Finnish (FIN)
AF:
AC:
7
AN:
15308
Middle Eastern (MID)
AF:
AC:
0
AN:
1366
European-Non Finnish (NFE)
AF:
AC:
8
AN:
310360
Other (OTH)
AF:
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
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000254 AC: 10AN: 39438Hom.: 1 Cov.: 1 AF XY: 0.000260 AC XY: 5AN XY: 19264 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
10
AN:
39438
Hom.:
Cov.:
1
AF XY:
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:
AC:
2
AN:
10798
American (AMR)
AF:
AC:
1
AN:
3010
Ashkenazi Jewish (ASJ)
AF:
AC:
1
AN:
534
East Asian (EAS)
AF:
AC:
0
AN:
1434
South Asian (SAS)
AF:
AC:
0
AN:
1710
European-Finnish (FIN)
AF:
AC:
1
AN:
2440
Middle Eastern (MID)
AF:
AC:
0
AN:
54
European-Non Finnish (NFE)
AF:
AC:
4
AN:
18850
Other (OTH)
AF:
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
Alfa
AF:
Hom.:
ExAC
AF:
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
PhyloP100
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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