rs121908159

Variant names:

• chr10-14953908-G-C
• rs121908159
• NM_001033855.3:c.103C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_Moderate PP1 PM2_Supporting PS3_Moderate PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.103C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Histidine by Aspartic Acid at amino acid 35 (p.His35Asp).The highest population minor allele frequency in gnomAD v4 is 0.000003100 (8/1111884 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.3) and DNA repair (36h after IR): Mean (SD): 27.29 (16.57). PS3 is Met at a moderate level (PMID:25917813).This variant has been detected in at least 4 individuals with SCID. Of those individuals, 02 were compound heterozygous for the variants: c.2T>C (p.Met1Thr) VUS according to SCID VCEP, 0.25pts AND p.L187*; Pathogenic according to the SCID VCEP specifications, 1 point. 02 individuals were homozygous for the variants (1 point). The total is 2.25 points, PM3_Strong. (PMIDs: 24481607, 15731174, and 32441320).At least one patient with this variant displayed T-B-NK+ (0.5 pts) + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + Family history of SCID (0.5 pts) + SCID gene panel or exome/genome sequencing conducted (0.5 pts), totaling 2 points, which is highly specific for SCID (PP4_Moderate, PMID:24481607).In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM3_Strong, PS3_Moderate, PP1_Supporting, PP4_Moderate, and PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA117007/MONDO:0011225/116

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 8.76
• Publications: 6 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 10 ACMG points.

• 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.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	NM_001033855.3	MANE Select	c.103C>G	p.His35Asp	missense	Exon 1 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.103C>G	p.His35Asp	missense	Exon 1 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.-102C>G		5_prime_UTR	Exon 1 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.103C>G	p.His35Asp	missense	Exon 1 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.103C>G	p.His35Asp	missense	Exon 1 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.103C>G		non_coding_transcript_exon	Exon 1 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250490 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Histiocytic medullary reticulosis (3)
2	-	-	Severe combined immunodeficiency due to DCLRE1C deficiency (2)
1	-	-	not provided (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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.91		Loss of MoRF binding (P = 0.0523)
MVP		1.0
MPC		0.34
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.057	Neutral
Varity_R		0.99
gMVP		0.98
Mutation Taster		=4/96	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: rs121908159; hg19: chr10-14995907;