NM_001033855.3:c.536G>T

Variant names:

• chr10-14934704-C-A
• rs150854849
• NM_001033855.3:c.536G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001033855.3(DCLRE1C):​c.536G>T​(p.Arg179Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense, splice_region
• Scores: Splicing: ADA: 0.9782
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.536G>T	p.Arg179Leu	missense splice_region	Exon 7 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.536G>T	p.Arg179Leu	missense splice_region	Exon 7 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.191G>T	p.Arg64Leu	missense splice_region	Exon 5 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.536G>T	p.Arg179Leu	missense splice_region	Exon 7 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.536G>T	p.Arg179Leu	missense splice_region	Exon 7 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*194G>T		splice_region non_coding_transcript_exon	Exon 5 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461494 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727064

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111668

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.54		Loss of disorder (P = 0.072)
MVP		0.98
MPC		0.33
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.89
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.85
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: rs150854849; hg19: chr10-14976703;