rs750695358

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001033855.3(DCLRE1C):​c.678+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

DCLRE1C
NM_001033855.3 splice_donor_5th_base, intron

Scores

2
Splicing: ADA: 0.1052
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -2.60
Variant links:
Genes affected
DCLRE1C (HGNC:17642): (DNA cross-link repair 1C) This gene encodes a nuclear protein that is involved in V(D)J recombination and DNA repair. The encoded protein has single-strand-specific 5'-3' exonuclease activity; it also exhibits endonuclease activity on 5' and 3' overhangs and hairpins. The protein also functions in the regulation of the cell cycle in response to DNA damage. Mutations in this gene can cause Athabascan-type severe combined immunodeficiency (SCIDA) and Omenn syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DCLRE1CNM_001033855.3 linkuse as main transcriptc.678+5G>T splice_donor_5th_base_variant, intron_variant ENST00000378278.7 NP_001029027.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DCLRE1CENST00000378278.7 linkuse as main transcriptc.678+5G>T splice_donor_5th_base_variant, intron_variant 1 NM_001033855.3 ENSP00000367527 P2Q96SD1-1

Frequencies

GnomAD3 genomes
AF:
0.0000330
AC:
5
AN:
151590
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000485
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000442
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000359
AC:
9
AN:
251030
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135720
show subpopulations
Gnomad AFR exome
AF:
0.0000621
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000704
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000117
AC:
171
AN:
1461802
Hom.:
0
Cov.:
43
AF XY:
0.000105
AC XY:
76
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000152
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000330
AC:
5
AN:
151590
Hom.:
0
Cov.:
31
AF XY:
0.0000405
AC XY:
3
AN XY:
74022
show subpopulations
Gnomad4 AFR
AF:
0.0000485
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000442
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Histiocytic medullary reticulosis Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Severe combined immunodeficiency due to DCLRE1C deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 14, 2018This sequence change falls in intron 8 of the DCLRE1C gene. It does not directly change the encoded amino acid sequence of the DCLRE1C protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs750695358, ExAC 0.01%). This variant has not been reported in the literature in individuals with DCLRE1C-related disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.76
CADD
Benign
0.0020
DANN
Benign
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.11
dbscSNV1_RF
Benign
0.40
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs750695358; hg19: chr10-14976374; API