chr10-14908583-C-CT

Variant names:

• chr10-14908583-C-CT
• rs760288938
• NM_001033855.3:c.1903dupA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_Moderate BS1_Supporting BS2

The NM_001033855.3(DCLRE1C):​c.1903dupA​(p.Ser635LysfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,614,130 control chromosomes in the GnomAD database, including 2 homozygotes. 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 NM_001033855.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.0370

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0847 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000243 (37/152258) while in subpopulation SAS AF= 0.00104 (5/4822). 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCLRE1C	NM_001033855.3	c.1903dupA	p.Ser635LysfsTer6	frameshift_variant	Exon 14 of 14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.1903dupA	p.Ser635LysfsTer6	frameshift_variant	Exon 14 of 14	1	NM_001033855.3	ENSP00000367527.2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152140 Hom.: 0 Cov.: 31

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: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000398 AC: 100 AN: 251198 Hom.: 0 AF XY: 0.000472 AC XY: 64 AN XY: 135730

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: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000228 AC: 333 AN: 1461872 Hom.: 2 Cov.: 32 AF XY: 0.000271 AC XY: 197 AN XY: 727236

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: 0.00115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.000255 AC XY: 19 AN XY: 74440

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

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: 0.000950

Bravo AF: 0.000189

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Nov 18, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation as the last 58 amino acids are lost and replaced with 5 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Observed previously in one patient with breast cancer (Lhota et al., 2016); This variant is associated with the following publications: (PMID: 33206719, 26822949) -

Aug 13, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe combined immunodeficiency due to DCLRE1C deficiency Uncertain:1 Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 18, 2022

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.1903dupA (p.Ser635LysfsX6) results in a premature termination codon located in exon 14 (i.e. in the last exon), therefore it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a C-terminal portion of the 692 amino acid long protein. One truncation downstream of this position has been reported in a homozygous individual affected with primary immunodeficiency (PMID: 32888943, through HGMD), however no further evidence details (e.g. phenotype severity) were provided on this case. The variant allele was found at a frequency of 0.0004 in 251198 control chromosomes, predominantly within the Ashkenazi Jewish and South Asian subpopulations with frequencies of 0.0024 and 0.001, respectively, in the gnomAD database (v2.1, exomes dataset). The observed variant frequencies within the Ashkenazi Jewish and South Asian control individuals are approximately 3.4 and 1.4 fold higher (respectively) than the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in DCLRE1C causing Severe Combined Immunodeficiency phenotype (0.00071), suggesting that the variant is a benign polymorphism. In addition, the variant was also reported in the Turkish population in individuals undergoing whole exome- or genome sequencing, who had unrelated phenotypes to the variant, with a frequency of 0.0019, which is about 2.7 fold higher than the MPAF. To our knowledge, no occurrence of c.1903dupA in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. An in vitro functional study examined several truncations upstream from our variant, and found that they retained relatively high residual activity levels (50-98%), however, no clear correlation was observed with the level of residual activity and the position of the truncations, therefore it is not possible to make clear conclusions about the variant effect for a truncation located a downstream from the examined variants. Authors of this study also noted that the observed hypomorphic effect for C-terminal truncations was consistent with a less severe phenotype in several reported cases who had these variants in homozygous state (PMID: 25917813). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as likely benign (n=1) and VUS (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Severe combined immunodeficiency due to DCLRE1C deficiency;C2700553:Histiocytic medullary reticulosis Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DCLRE1C NM_001033855.2 exon 14 p.Ser635Lysfs*6 (c.1903dupA): This variant has been reported in the literature in 1 individual with breast cancer (Lhota 2016 PMID:26822949). This variant is present in 0.2% (24/10360) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/10-14950582-C-CT?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:468484). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a duplication of 1 nucleotide at position 1903. This variant creates a premature stop codon 6 amino acids downstream from this location which results in an absent or abnormal protein. However, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. Variants occuring in this region have been reported to retain high activity levels potentially consistent with a less severe phenotype (Felgentreff 2016 PMID: 25917813). Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs760288938; hg19: chr10-14950582;