10-14932844-G-A

Variant names:

• chr10-14932844-G-A
• rs35927251
• NM_001033855.3:c.780+10C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001033855.3(DCLRE1C):​c.780+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,612,202 control chromosomes in the GnomAD database, including 24,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2351 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22047 hom.)
• Consequence: DCLRE1C NM_001033855.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.75
• Publications: 12 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 10-14932844-G-A is Benign according to our data. Variant chr10-14932844-G-A is described in ClinVar as Benign. ClinVar VariationId is 257181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

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.780+10C>T		intron	N/A	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.780+10C>T		intron	N/A	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.435+10C>T		intron	N/A	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.780+10C>T		intron	N/A	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.780+10C>T		intron	N/A	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*438+10C>T		intron	N/A	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26414 AN: 151960 Hom.: 2345 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0968

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.166 AC: 41658 AN: 251442 AF XY: 0.161

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.171 AC: 250280 AN: 1460122 Hom.: 22047 Cov.: 32 AF XY: 0.169 AC XY: 122867 AN XY: 726424

African (AFR) AF: 0.193 AC: 6469 AN: 33462

American (AMR) AF: 0.234 AC: 10476 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3172 AN: 26128

East Asian (EAS) AF: 0.0978 AC: 3884 AN: 39698

South Asian (SAS) AF: 0.129 AC: 11101 AN: 86222

European-Finnish (FIN) AF: 0.154 AC: 8233 AN: 53416

Middle Eastern (MID) AF: 0.196 AC: 1131 AN: 5764

European-Non Finnish (NFE) AF: 0.176 AC: 195561 AN: 1110384

Other (OTH) AF: 0.170 AC: 10253 AN: 60332

GnomAD4 genome AF: 0.174 AC: 26450 AN: 152080 Hom.: 2351 Cov.: 32 AF XY: 0.175 AC XY: 12995 AN XY: 74328

African (AFR) AF: 0.185 AC: 7689 AN: 41452

American (AMR) AF: 0.210 AC: 3200 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3472

East Asian (EAS) AF: 0.0962 AC: 499 AN: 5186

South Asian (SAS) AF: 0.124 AC: 598 AN: 4830

European-Finnish (FIN) AF: 0.166 AC: 1754 AN: 10576

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11745 AN: 67990

Other (OTH) AF: 0.163 AC: 343 AN: 2108

Alfa AF: 0.156 Hom.: 1104

Bravo AF: 0.180

Asia WGS AF: 0.109 AC: 379 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Histiocytic medullary reticulosis (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Severe combined immunodeficiency due to DCLRE1C deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	13
DANN	Benign	0.46
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.55		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35927251; hg19: chr10-14974843; COSMIC: COSV63183107; COSMIC: COSV63183107;