10-14926856-G-A

Variant names:

• chr10-14926856-G-A
• rs41298896
• NM_001033855.3:c.959C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001033855.3(DCLRE1C):​c.959C>T​(p.Ser320Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S320C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.99
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

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.959C>T	p.Ser320Phe	missense	Exon 11 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.959C>T	p.Ser320Phe	missense	Exon 11 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.614C>T	p.Ser205Phe	missense	Exon 9 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.959C>T	p.Ser320Phe	missense	Exon 11 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.959C>T	p.Ser320Phe	missense	Exon 11 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*617C>T		non_coding_transcript_exon	Exon 9 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460866 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726810

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111150

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.65		Loss of disorder (P = 0.0164)
MVP		0.94
MPC		0.31
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.92
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs41298896; hg19: chr10-14968855;