rs144654282

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The ENST00000378278.7(DCLRE1C):​c.1368C>T​(p.Asn456=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,614,172 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

DCLRE1C
ENST00000378278.7 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.33
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 Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
Variant 10-14909119-G-A is Benign according to our data. Variant chr10-14909119-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 299315.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
BP7
Synonymous conserved (PhyloP=1.33 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000243 (37/152302) while in subpopulation SAS AF= 0.00104 (5/4828). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DCLRE1CNM_001033855.3 linkuse as main transcriptc.1368C>T p.Asn456= synonymous_variant 14/14 ENST00000378278.7 NP_001029027.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DCLRE1CENST00000378278.7 linkuse as main transcriptc.1368C>T p.Asn456= synonymous_variant 14/141 NM_001033855.3 ENSP00000367527 P2Q96SD1-1

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152184
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000394
AC:
99
AN:
251248
Hom.:
0
AF XY:
0.000464
AC XY:
63
AN XY:
135778
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00238
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00101
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000211
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.000226
AC:
330
AN:
1461870
Hom.:
2
Cov.:
32
AF XY:
0.000267
AC XY:
194
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00172
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00114
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000102
Gnomad4 OTH exome
AF:
0.000811
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
152302
Hom.:
0
Cov.:
31
AF XY:
0.000255
AC XY:
19
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000584
Hom.:
0
Bravo
AF:
0.000189
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000545
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Histiocytic medullary reticulosis Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabMay 18, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2020- -
Severe combined immunodeficiency due to DCLRE1C deficiency Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
CADD
Benign
7.3
DANN
Benign
0.74

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

LitVar

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

Other links and lift over

dbSNP: rs144654282; hg19: chr10-14951118; API