rs147013097

Variant names:

• chr10-14945139-G-A
• rs147013097
• NM_001033855.3:c.212C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-14945139-G-A
• chr10-14945139-G-C
• chr10-14945139-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The c.212C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Methionine at amino acid 71 (p.Thr71Met).The filtering allele frequency (the upper threshold of the 95% CI of 303/1179486 alleles) of the c.212C>T variant in DCLRE1C is 0.0002288 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies.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): No criteria were applied. LINK:https://erepo.genome.network/evrepo/ui/classification/CA5416976/MONDO:0011225/116

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: DCLRE1C NM_022487.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 3.96
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

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.212C>T	p.Thr71Met	missense	Exon 3 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001289078.2		c.-78C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001276007.1	Q96SD1-3
	DCLRE1C	NM_022487.4		c.-78C>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.212C>T	p.Thr71Met	missense	Exon 3 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.212C>T	p.Thr71Met	missense	Exon 3 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000378246.6	TSL:1	n.212C>T		non_coding_transcript_exon	Exon 3 of 13	ENSP00000367492.3	A0A8V8TKP5

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 151920 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000147 AC: 37 AN: 251194 AF XY: 0.000162

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000218 AC: 319 AN: 1460640 Hom.: 0 Cov.: 30 AF XY: 0.000238 AC XY: 173 AN XY: 726532

African (AFR) AF: 0.0000598 AC: 2 AN: 33450

American (AMR) AF: 0.000313 AC: 14 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85856

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000254 AC: 282 AN: 1111506

Other (OTH) AF: 0.000182 AC: 11 AN: 60326

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152038 Hom.: 0 Cov.: 30 AF XY: 0.000215 AC XY: 16 AN XY: 74332

African (AFR) AF: 0.0000482 AC: 2 AN: 41486

American (AMR) AF: 0.000328 AC: 5 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67980

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000265 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000219

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Severe combined immunodeficiency due to DCLRE1C deficiency (2)
-	1	-	Athabaskan severe combined immunodeficiency (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	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.067	D
MutationAssessor	Benign	1.3	L
PhyloP100		4.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.91
MPC		0.074
ClinPred		0.13	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.43
Mutation Taster		=80/20	polymorphism

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: rs147013097; hg19: chr10-14987138;