NM_001033855.3:c.1284A>C

Variant names:

• chr10-14909203-T-G
• rs113870881
• NM_001033855.3:c.1284A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: NM_001033855.3(DCLRE1C):c.1284A>C is a missense variant predicted to cause substitution of Lysine by Asparagine at amino acid 428 (p.Lys428Asn).The filtering allele frequency (the lower threshold of the 95% CI of 501/75018) of the c.1284A>C variant in DCLRE1C is 0.005719 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00346) for BA1, and therefore meets this criterion (BA1). Additionally, 2 homozygous adults are reported in gnomAD v.4 in the same population. BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5416508/MONDO:0011225/116

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: -0.817
• Publications: 1 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 -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1284A>C	p.Lys428Asn	missense	Exon 14 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.1284A>C	p.Lys428Asn	missense	Exon 14 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.939A>C	p.Lys313Asn	missense	Exon 12 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.1284A>C	p.Lys428Asn	missense	Exon 14 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.1157-9891A>C		intron	N/A	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*942A>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 302 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00681

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000526 AC: 132 AN: 251062 AF XY: 0.000310

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000213 AC: 311 AN: 1461828 Hom.: 2 Cov.: 32 AF XY: 0.000166 AC XY: 121 AN XY: 727214

African (AFR) AF: 0.00642 AC: 215 AN: 33476

American (AMR) AF: 0.000492 AC: 22 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111982

Other (OTH) AF: 0.000431 AC: 26 AN: 60394

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74430

African (AFR) AF: 0.00688 AC: 286 AN: 41542

American (AMR) AF: 0.000589 AC: 9 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.00226

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	Severe combined immunodeficiency due to DCLRE1C deficiency (3)
-	-	2	not specified (2)
-	-	1	DCLRE1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.48
DANN	Benign	0.51
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.82
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.028
Sift	Benign	0.62	T
Sift4G	Benign	0.51	T
Polyphen		0.0030	B
Vest4		0.046
MutPred		0.32		Loss of methylation at K428 (P = 0.0031)
MVP		0.53
MPC		0.048
ClinPred		0.0094	T
GERP RS		-2.0
Varity_R		0.060
gMVP		0.067
Mutation Taster		=82/18	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: rs113870881; hg19: chr10-14951202;