rs121908158

Variant names:

• chr10-14954009-A-G
• rs121908158
• NM_001033855.3:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP1 PP4 PM2_Supporting PVS1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2T>C (p.Met1Thr) (NM_001033855.3) is a missense variant predictedto cause the substitution of Methionine by Threonine at amino acid 1 (p.Met1Thr). The next possible initiation codon is at codon 8. This region does not contain known pathogenic/likely pathogenic variants, PVS1_Supporting.The highest population minor allele frequency in gnomAD v4 is 0.00001470 (1/68040 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting).At least one patient was observed in the literature (PMID:15731174) presenting: * Diagnostic criteria for Omenn syndrome (0.5pt) + * Increased cellular radiosensitivity (0.5pt) = total 1 point, PP4_Supporting. The variant has been reported to segregate with OS in - at least - 02 affected family members (proband + one brother) from one family (PP1_Supporting). The patient also had another affected brother without genomic information (PMID:15731174).This patient is compound heterozygous with c.103C>G (H35D). Phase is confirmed; Pathogenic according to the SCID VCEP specifications; Not counted here to avoid circularity.Two functional assays were found: PMID:15731174 shows that the ARTEMIS variant (M1T) resulted in a V(D)J recombination efficiency of 2.1% to 2.7%. This corresponds to a recombination efficiency of between 37% and 48% when compared with the assay with WT-ARTEMIS (Which is higher than our threshold, 25%. In the second reference, the activity levels (in % of WT activity) are Recombination (Mean, SD): 80.41, 4.77 and DNA repair (Mean, SD): 76.04, 6.43. Both exceed the established threshold for PS3 (<25% of wild-type activity). With this, PS3 is not applied at any level of evidence.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: (specification version 1.0): PVS1_Supporting, PM2_Supporting, PP1_Supporting, and PP4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA117009/MONDO:0011225/116

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DCLRE1C NM_001033855.3 start_lost
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 8.17
• Publications: 1 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]

MEIG1 (HGNC:23429): (meiosis/spermiogenesis associated 1) Predicted to act upstream of or within cellular protein localization; manchette assembly; and sperm axoneme assembly. Predicted to be located in cytosol and manchette. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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.2T>C	p.Met1?	start_lost	Exon 1 of 14	NP_001029027.1
	DCLRE1C	NM_001350965.2		c.2T>C	p.Met1?	start_lost	Exon 1 of 15	NP_001337894.1
	DCLRE1C	NR_110297.2		n.88T>C		non_coding_transcript_exon	Exon 1 of 17

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	ENSP00000367527.2
	DCLRE1C	ENST00000378289.8	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	ENSP00000367538.4
	DCLRE1C	ENST00000357717.6	TSL:1	n.2T>C		non_coding_transcript_exon	Exon 1 of 12	ENSP00000350349.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Histiocytic medullary reticulosis Pathogenic:1

Jun 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Severe combined immunodeficiency due to DCLRE1C deficiency Uncertain:1

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.2T>C (p.Met1Thr) (NM_001033855.3) is a missense variant predicted to cause the substitution of Methionine by Threonine at amino acid 1 (p.Met1Thr). The next possible initiation codon is at codon 8. This region does not contain known pathogenic/likely pathogenic variants, PVS1_Supporting. The highest population minor allele frequency in gnomAD v4 is 0.00001470 (1/68040 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient was observed in the literature (PMID: 15731174) presenting: * Diagnostic criteria for Omenn syndrome (0.5pt) + * Increased cellular radiosensitivity (0.5pt) = total 1 point, PP4_Supporting. The variant has been reported to segregate with OS in - at least - 02 affected family members (proband + one brother) from one family (PP1_Supporting). The patient also had another affected brother without genomic information (PMID: 15731174). This patient is compound heterozygous with c.103C>G (H35D). Phase is confirmed; Pathogenic according to the SCID VCEP specifications; Not counted here to avoid circularity. Two functional assays were found: PMID: 15731174 shows that the ARTEMIS variant (M1T) resulted in a V(D)J recombination efficiency of 2.1% to 2.7%. This corresponds to a recombination efficiency of between 37% and 48% when compared with the assay with WT-ARTEMIS (Which is higher than our threshold, 25%. In the second reference, the activity levels (in % of WT activity) are Recombination (Mean, SD): 80.41, 4.77 and DNA repair (Mean, SD): 76.04, 6.43. Both exceed the established threshold for PS3 (<25% of wild-type activity). With this, PS3 is not applied at any level of evidence. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: (specification version 1.0): PVS1_Supporting, PM2_Supporting, PP1_Supporting, and PP4_Supporting.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Uncertain	0.75	D
PhyloP100		8.2
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		1.0		Gain of glycosylation at M1 (P = 0.0099)
MVP		0.99
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.029	Neutral
Varity_R		0.96
gMVP		0.88
Mutation Taster		=3/197	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: rs121908158; hg19: chr10-14996008;