10-14945182-C-A

Variant names:

• chr10-14945182-C-A
• rs138077101
• NM_001033855.3:c.169G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The c.169G>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause a substitution of Valine by Phenylalanine at amino acid 57 (p.Val57Phe).The popmax filtering allele frequency in gnomAD v2.1. is 0.0001675 (based on 29/128916 alleles in the non-Finnish European population), which is below the SCID VCEP established threshold of >0.00078.However, the highest MAF is in the Ashkenazi Jewish population at 0.005896 (61/10346 alleles and NO homozygotes reported), which is above the SCID VCEP established threshold of >00078. As this population is not known to have a higher disease prevalence, this is considered to meet BS1.After a comprehensive literature search, the variant has not been found in individuals with SCID due to DCLRE1C deficiency.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5416981/MONDO:0011225/116

• Frequency:
  • Genomes: 𝑓 0.00072 (4 hom., cov: 30)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:4
• Conservation: PhyloP100: 2.99
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: 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.169G>T	p.Val57Phe	missense	Exon 3 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.169G>T	p.Val57Phe	missense	Exon 3 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289078.2		c.-121G>T		5_prime_UTR	Exon 2 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.169G>T	p.Val57Phe	missense	Exon 3 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.169G>T	p.Val57Phe	missense	Exon 3 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000378246.6	TSL:1	n.169G>T		non_coding_transcript_exon	Exon 3 of 13	ENSP00000367492.3	A0A8V8TKP5

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152054 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000375 AC: 94 AN: 250552 AF XY: 0.000428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000212 AC: 309 AN: 1460044 Hom.: 0 Cov.: 30 AF XY: 0.000251 AC XY: 182 AN XY: 726236

African (AFR) AF: 0.0000299 AC: 1 AN: 33422

American (AMR) AF: 0.000134 AC: 6 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00552 AC: 144 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.0000816 AC: 7 AN: 85796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111224

Other (OTH) AF: 0.000348 AC: 21 AN: 60266

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152168 Hom.: 4 Cov.: 30 AF XY: 0.000685 AC XY: 51 AN XY: 74416

African (AFR) AF: 0.0000241 AC: 1 AN: 41518

American (AMR) AF: 0.000196 AC: 3 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.000865

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Histiocytic medullary reticulosis (2)
-	-	2	Severe combined immunodeficiency due to DCLRE1C deficiency (2)
-	1	-	Athabaskan severe combined immunodeficiency (1)
-	-	1	DCLRE1C-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.030	T
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.014	D
Sift4G	Benign	0.22	T
Polyphen		0.90	P
Vest4		0.78
MVP		0.91
MPC		0.33
ClinPred		0.15	T
GERP RS		5.2
Varity_R		0.85
gMVP		0.91
Mutation Taster		=172/128	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: rs138077101; hg19: chr10-14987181;