NM_001033855.3:c.1893C>T

Variant names:

• chr10-14908594-G-A
• rs41300676
• NM_001033855.3:c.1893C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001033855.3(DCLRE1C):​c.1893C>T​(p.Pro631Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,614,068 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P631P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (29 hom.)
• Consequence: DCLRE1C NM_001033855.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.839
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-14908594-G-A is Benign according to our data. Variant chr10-14908594-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.839 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00439 (668/152202) while in subpopulation NFE AF = 0.00629 (428/68016). AF 95% confidence interval is 0.0058. There are 3 homozygotes in GnomAd4. There are 310 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1893C>T	p.Pro631Pro	synonymous	Exon 14 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001289076.2		c.1548C>T	p.Pro516Pro	synonymous	Exon 12 of 12	NP_001276005.1	Q96SD1-3
	DCLRE1C	NM_001289078.2		c.1548C>T	p.Pro516Pro	synonymous	Exon 12 of 12	NP_001276007.1	Q96SD1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.1893C>T	p.Pro631Pro	synonymous	Exon 14 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.1157-9282C>T		intron	N/A	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*1551C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152084 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00375 AC: 942 AN: 251202 AF XY: 0.00355

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00568 AC: 8299 AN: 1461866 Hom.: 29 Cov.: 32 AF XY: 0.00550 AC XY: 4002 AN XY: 727234

African (AFR) AF: 0.00305 AC: 102 AN: 33478

American (AMR) AF: 0.00340 AC: 152 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00559 AC: 146 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39690

South Asian (SAS) AF: 0.00176 AC: 152 AN: 86256

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00665 AC: 7396 AN: 1112004

Other (OTH) AF: 0.00520 AC: 314 AN: 60396

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152202 Hom.: 3 Cov.: 31 AF XY: 0.00417 AC XY: 310 AN XY: 74418

African (AFR) AF: 0.00248 AC: 103 AN: 41532

American (AMR) AF: 0.00569 AC: 87 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4814

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00629 AC: 428 AN: 68016

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00508 Hom.: 2

Bravo AF: 0.00472

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00581

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Histiocytic medullary reticulosis (2)
-	-	1	Severe combined immunodeficiency due to DCLRE1C deficiency (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
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.0
DANN	Benign	0.52
PhyloP100		0.84
Mutation Taster		=98/2	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: rs41300676; hg19: chr10-14950593;