chr10-14909130-CACAATCT-C

Variant names:

• chr10-14909130-CACAATCT-C
• rs786200884
• NM_001033855.3:c.1350_1356delAGATTGT

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001033855.3(DCLRE1C):​c.1350_1356delAGATTGT​(p.Asp451LysfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000766512: Experimental studies have shown that this variant results in reduced recombination activity, reduced DNA repair activity (following ionizing radiation), and elevated interchromosomal V(D)J rearrangements when compared to wildtype (PMID:25917813, 21147755).". The gene DCLRE1C is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DCLRE1C NM_001033855.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.42
• Publications: 2 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, Orphanet, Ambry Genetics
• severe combined immunodeficiency due to DCLRE1C deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Specifications for DCLRE1C are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 22 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. There are 42 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000766512: Experimental studies have shown that this variant results in reduced recombination activity, reduced DNA repair activity (following ionizing radiation), and elevated interchromosomal V(D)J rearrangements when compared to wildtype (PMID: 25917813, 21147755).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-14909130-CACAATCT-C is Pathogenic according to our data. Variant chr10-14909130-CACAATCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	NM_001033855.3	MANE Select	c.1350_1356delAGATTGT	p.Asp451LysfsTer11	frameshift	Exon 14 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.1350_1356delAGATTGT	p.Asp451LysfsTer11	frameshift	Exon 14 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.1005_1011delAGATTGT	p.Asp336LysfsTer11	frameshift	Exon 12 of 12	NP_001276005.1	Q96SD1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.1350_1356delAGATTGT	p.Asp451LysfsTer11	frameshift	Exon 14 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.1157-9825_1157-9819delAGATTGT		intron	N/A	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*1008_*1014delAGATTGT		non_coding_transcript_exon	Exon 12 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Athabaskan severe combined immunodeficiency (1)
1	-	-	Histiocytic medullary reticulosis (1)
1	-	-	Severe combined immunodeficiency due to DCLRE1C deficiency (1)
1	-	-	Severe combined immunodeficiency, partial (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786200884; hg19: chr10-14951129;