NM_001033855.3:c.194C>T

Variant names:

• chr10-14945157-G-A
• rs886037925
• NM_001033855.3:c.194C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4_Moderate PM2_Supporting PP1_Strong PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.194C>T(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 65 p.Thr65Ile.This variant is absent from gnomAD v2.1.1 (PM2_Supporting).This variant has been detected in at least 13 individuals with SCID/Lealy SCID/Omen. Of those individuals, 2 were compound heterozygous for the variant p.T577Nfs*21 (Likely Pathogenic according to the SCID VCEP specifications - confirmed in trans by family testing (PMID:26476407, 2 pts). 10 individuals were homozygous for the variant (1 point limit was reached - PMID:26476407) (PM3_moderate); For 1 individual (PMID:25917813), the second allele information wasn't available. The variant has been reported to segregate with SCID in 7 affected family members from 3 families (Family A: Proband + 4; Family D: Proband + 2; Family E: Proband + 1 = 7 segregations, LOD: 4.21); PP1_Strong; PMID:26476407). At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P1, 2 and 5, 2 pts, PMID:26476407, PP4_moderate).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, PP4_Moderate, PP1_Strong, PM3_Strong, PM2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586373/MONDO:0011225/116

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 6.51
• 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, 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: Pathogenic. The variant received 11 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	NM_001033855.3	MANE Select	c.194C>T	p.Thr65Ile	missense	Exon 3 of 14	NP_001029027.1
	DCLRE1C	NM_001350965.2		c.194C>T	p.Thr65Ile	missense	Exon 3 of 15	NP_001337894.1
	DCLRE1C	NR_110297.2		n.365C>T		non_coding_transcript_exon	Exon 4 of 17

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.194C>T	p.Thr65Ile	missense	Exon 3 of 14	ENSP00000367527.2
	DCLRE1C	ENST00000378289.8	TSL:1	c.194C>T	p.Thr65Ile	missense	Exon 3 of 14	ENSP00000367538.4
	DCLRE1C	ENST00000378246.6	TSL:1	n.194C>T		non_coding_transcript_exon	Exon 3 of 13	ENSP00000367492.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251234 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460858 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726682

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111588

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Severe combined immunodeficiency due to DCLRE1C deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.74		Gain of helix (P = 0.062)
MVP		0.98
MPC		0.31
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.91
Mutation Taster		=197/103	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: rs886037925; hg19: chr10-14987156;