rs886037924

Variant names:

• chr10-14908817-G-GT
• rs886037924
• NM_001033855.3:c.1669dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4_Moderate PP1 PM2_Supporting PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_001033855.3(DCLRE1C):c.1669dup (p.Thr557AsnfsTer21) variant in DCLRE1C is a frameshift variant that may cause loss of function of the protein; however, it is predicted that the transcript likely escapes nonsense-mediated decay (PMID:26476407 supports this notion). Additionally, no downstream pathogenic variants have been curated to date (curated following SCID VCEP specifications). Thus, currently, this variant is limited to PVS1 at moderate strength.This variant is absent from gnomAD v2.1.1 (PM2_Supporting).There are 2 patients who are siblings (Family A, P4, and P5) (PMID:26476407, PP1_supporting).At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P5, 2 pts, PMID:26476407, PP4_Moderate).In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied: PVS1_Moderate, PM2_Supporting, PP1_Supporting, and PP4_Moderate, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586372/MONDO:0011225/116

• Frequency: Genomes: not found (cov: 31)
• Consequence: DCLRE1C NM_001033855.3 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.83
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	NM_001033855.3	MANE Select	c.1669dupA	p.Thr557AsnfsTer21	frameshift	Exon 14 of 14	NP_001029027.1
	DCLRE1C	NM_001350965.2		c.1669dupA	p.Thr557AsnfsTer21	frameshift	Exon 14 of 15	NP_001337894.1
	DCLRE1C	NM_001289076.2		c.1324dupA	p.Thr442AsnfsTer21	frameshift	Exon 12 of 12	NP_001276005.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.1669dupA	p.Thr557AsnfsTer21	frameshift	Exon 14 of 14	ENSP00000367527.2
	DCLRE1C	ENST00000357717.6	TSL:1	n.*1327dupA		non_coding_transcript_exon	Exon 12 of 12	ENSP00000350349.3
	DCLRE1C	ENST00000378246.6	TSL:1	n.*1286dupA		non_coding_transcript_exon	Exon 13 of 13	ENSP00000367492.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Severe combined immunodeficiency due to DCLRE1C deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886037924; hg19: chr10-14950816;