10-14935470-C-T

Variant names:

• chr10-14935470-C-T
• rs41297018
• NM_001033855.3:c.457G>A

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: The c.457G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Arginine at amino acid 153 (p.Gly153Arg).The filtering allele frequency (the lower threshold of the 95% CI of 2195/129158) of the c.457G>A variant in DCLRE1C is 0.01641 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold >0.00346 for BA1, and therefore meets this criterion (BA1). Also, nineteen (19) adult homozygous individuals with this variant are present in gnomADv2.1.1 (European non-Finnish n=15, European (Finnish) n=1, Latino/Admixed American n=1, South Asian n=2)(BS2_Supporting).Additionally, a functional study showed non-dysfunction of V(D)J recombination and DNA repair (around 100% compared to wild type), and we do not find this variant described in patients with SCID due to DCLRE1C deficiency after a comprehensive literature search.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA213680/MONDO:0011225/116

• Frequency:
  • Genomes: 𝑓 0.0094 (15 hom., cov: 31)
  • Exomes 𝑓: 0.013 (155 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:13
• Conservation: PhyloP100: 7.43
• Publications: 13 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.457G>A	p.Gly153Arg	missense	Exon 6 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.457G>A	p.Gly153Arg	missense	Exon 6 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.112G>A	p.Gly38Arg	missense	Exon 4 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.457G>A	p.Gly153Arg	missense	Exon 6 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.457G>A	p.Gly153Arg	missense	Exon 6 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*115G>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes AF: 0.00939 AC: 1429 AN: 152120 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00695

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0104 AC: 2609 AN: 251430 AF XY: 0.0104

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.00873

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00651

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0132 AC: 19222 AN: 1461612 Hom.: 155 Cov.: 31 AF XY: 0.0130 AC XY: 9440 AN XY: 727128

African (AFR) AF: 0.00194 AC: 65 AN: 33476

American (AMR) AF: 0.00523 AC: 234 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00961 AC: 251 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00611 AC: 527 AN: 86252

European-Finnish (FIN) AF: 0.00674 AC: 360 AN: 53410

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.0154 AC: 17105 AN: 1111784

Other (OTH) AF: 0.0106 AC: 643 AN: 60380

GnomAD4 genome AF: 0.00939 AC: 1430 AN: 152238 Hom.: 15 Cov.: 31 AF XY: 0.00922 AC XY: 686 AN XY: 74432

African (AFR) AF: 0.00236 AC: 98 AN: 41552

American (AMR) AF: 0.00694 AC: 106 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4816

European-Finnish (FIN) AF: 0.00669 AC: 71 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0159 AC: 1084 AN: 68014

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0136 Hom.: 35

Bravo AF: 0.00908

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0111 AC: 1342

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0147

EpiControl AF: 0.0143

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	1	3	Severe combined immunodeficiency due to DCLRE1C deficiency (4)
-	-	1	Histiocytic medullary reticulosis (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
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0095	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.60
Sift	Benign	0.083	T
Sift4G	Uncertain	0.049	D
Polyphen		0.84	P
Vest4		0.28
MutPred		0.82		Loss of sheet (P = 0.0037)
MPC		0.28
ClinPred		0.032	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.84
Mutation Taster		=86/14	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: rs41297018; hg19: chr10-14977469; COSMIC: COSV99064323;