rs41296438

chr10-14945124-C-Achr10-14945124-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001033855.3(DCLRE1C):c.227G>T(p.Arg76Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. R76T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24116394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLRE1C	NM_001033855.3	c.227G>T	p.Arg76Ile	missense_variant	3/14	ENST00000378278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.227G>T	p.Arg76Ile	missense_variant	3/14	1	NM_001033855.3	P2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460176 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726300

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	19
Dann	Benign	0.96
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.25
Sift	Benign	0.18	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.12	B;B
Vest4		0.46
MutPred		0.55		Loss of MoRF binding (P = 0.0125);Loss of MoRF binding (P = 0.0125);
MVP		0.75
MPC		0.21
ClinPred		0.61	D
GERP RS		2.3
Varity_R		0.28
gMVP		0.56

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

Other links and lift over

dbSNP: rs41296438; hg19: chr10-14987123; COSMIC: COSV63182744;