rs121908156

Variant names:

• chr10-14945110-G-A
• rs121908156
• NM_001033855.3:c.241C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-14945110-G-A
• chr10-14945110-G-T
• chr10-14945110-G-C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PP4 PS3_Moderate PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001033855.3:c.241C>T (p.Arg81Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 3/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The filtering allele frequency (the upper threshold of the 95% CI of 38/1177816 alleles) of the c.241C>T variant in DCLRE1C is 0.00002205 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).Activity levels in % of WT activity = Recombination: Mean (SD): 19.48 (1.56) and DNA repair (36h after IR): Mean (SD): 16.05 (4.77). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level. (PMID:25917813).At least one patient with this variant displayed Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, which is highly specific for SCID (PP4_Supporting, PMID:11336668). The proband (P2) is homozygous (Table 1) for this variant (0.5pt; PM3_Supporting).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM3_Supporting, PS3_Moderate, and PP4_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA117001/MONDO:0011225/116

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: DCLRE1C NM_022487.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 0.800
• Publications: 8 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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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_022487.4. 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.241C>T	p.Arg81*	stop_gained	Exon 3 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001289078.2		c.-49C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001276007.1	Q96SD1-3
	DCLRE1C	NM_022487.4		c.-49C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_071932.2	Q96SD1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.241C>T	p.Arg81*	stop_gained	Exon 3 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.241C>T	p.Arg81*	stop_gained	Exon 3 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000378246.6	TSL:1	n.241C>T		non_coding_transcript_exon	Exon 3 of 13	ENSP00000367492.3	A0A8V8TKP5

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151828 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250582 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 38 AN: 1457934 Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 20 AN XY: 725178

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.0000673 AC: 3 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1109836

Other (OTH) AF: 0.0000166 AC: 1 AN: 60200

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151828 Hom.: 0 Cov.: 30 AF XY: 0.0000540 AC XY: 4 AN XY: 74140

African (AFR) AF: 0.0000242 AC: 1 AN: 41318

American (AMR) AF: 0.0000657 AC: 1 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000664 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Severe combined immunodeficiency due to DCLRE1C deficiency (4)
3	-	-	not provided (3)
2	-	-	Histiocytic medullary reticulosis (2)
1	-	-	DCLRE1C-related disorder (1)
1	-	-	Severe combined immunodeficiency disease (1)
1	-	-	Severe combined immunodeficiency due to DCLRE1C deficiency;C2700553:Histiocytic medullary reticulosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.69	D
PhyloP100		0.80
Vest4		0.87
GERP RS		2.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs121908156; hg19: chr10-14987109;