rs757316102

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_001033855.3(DCLRE1C):c.350C>T is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 117 (p.Pro117Leu). The filtering allele frequency (the upper threshold of the 95% CI of 50/1178836) of the c.350C>T variant in DCLRE1C is 0.00003376 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore do not meet this criterion.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. LINK:https://erepo.genome.network/evrepo/ui/classification/CA5416895/MONDO:0011225/116

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

DCLRE1C
NM_001033855.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 8.69

Publications

2 publications found

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]

DCLRE1C Gene-Disease associations (from GenCC):

Omenn syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet
severe combined immunodeficiency due to DCLRE1C deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

DCLRE1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCLRE1C	NM_001033855.3 link	c.350C>T	p.Pro117Leu	missense_variant	Exon 5 of 14	ENST00000378278.7	NP_001029027.1	Q96SD1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7 link	c.350C>T	p.Pro117Leu	missense_variant	Exon 5 of 14	1	NM_001033855.3	ENSP00000367527.2		Q96SD1-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

251150

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1460542

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726656

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

1110890

Other (OTH)

AF:

0.0000166

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.0000198

AC:

AN:

151770

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74094

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41290

American (AMR)

AF:

0.00

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67946

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to DCLRE1C deficiency

Uncertain:2

Feb 15, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_001033855.3(DCLRE1C):c.350C>T is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 117 (p.Pro117Leu). The filtering allele frequency (the upper threshold of the 95% CI of 50/1178836) of the c.350C>T variant in DCLRE1C is 0.00003376 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore do not meet this criterion. To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): No criteria were applied. -

Sep 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline with leucine at codon 117 of the DCLRE1C protein (p.Pro117Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs757316102, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

not specified

Uncertain:1

Jan 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DCLRE1C c.350C>T (p.Pro117Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251150 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.350C>T in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Apr 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.350C>T (p.P117L) alteration is located in exon 5 (coding exon 5) of the DCLRE1C gene. This alteration results from a C to T substitution at nucleotide position 350, causing the proline (P) at amino acid position 117 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Athabaskan severe combined immunodeficiency

Uncertain:1

Apr 15, 2021

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Histiocytic medullary reticulosis

Uncertain:1

May 11, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Mar 02, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

.;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

8.7

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-8.2

D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.72

Gain of catalytic residue at P117 (P = 0.034);Gain of catalytic residue at P117 (P = 0.034);

MVP

0.98

MPC

0.30

ClinPred

0.99

GERP RS

5.4

Varity_R

0.93

gMVP

0.88

Mutation Taster

=149/151

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over