NM_001033855.3:c.212C>A

Variant names:

• chr10-14945139-G-T
• rs147013097
• NM_001033855.3:c.212C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001033855.3(DCLRE1C):​c.212C>A​(p.Thr71Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,654 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T71M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-14945140-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2136851.Status of the report is criteria_provided_single_submitter, 1 stars.

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.212C>A	p.Thr71Lys	missense	Exon 3 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.212C>A	p.Thr71Lys	missense	Exon 3 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289078.2		c.-78C>A		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.212C>A	p.Thr71Lys	missense	Exon 3 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.212C>A	p.Thr71Lys	missense	Exon 3 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000378246.6	TSL:1	n.212C>A		non_coding_transcript_exon	Exon 3 of 13	ENSP00000367492.3	A0A8V8TKP5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460654 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726540

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111518

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.32
Sift	Benign	0.099	T
Sift4G	Benign	0.93	T
Polyphen		0.54	P
Vest4		0.71
MutPred		0.44		Gain of MoRF binding (P = 0.0404)
MVP		0.83
MPC		0.11
ClinPred		0.69	D
GERP RS		4.3
Varity_R		0.21
gMVP		0.55
Mutation Taster		=80/20	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: rs147013097; hg19: chr10-14987138;