NM_001033855.3:c.2T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP1PP4PM2_SupportingPVS1_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

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1

Conservation

PhyloP100: 8.17

Variant links:

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 links:

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]

MEIG1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCLRE1C	NM_001033855.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	ENST00000378278.7	NP_001029027.1	Q96SD1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	1	NM_001033855.3	ENSP00000367527.2		Q96SD1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

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.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: reviewed by expert panel

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

.;D

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Uncertain

0.75

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

1.0

Gain of glycosylation at M1 (P = 0.0099);Gain of glycosylation at M1 (P = 0.0099);

MVP

0.99

ClinPred

1.0

GERP RS

5.5

Varity_R

0.96

gMVP

0.88

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over