rs774397708

Variant names:

• chr1-113905722-C-T
• rs774397708
• NM_022836.4:c.136C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001319946.2(DCLRE1B):​c.-77C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000821 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DCLRE1B NM_001319946.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.43

Genes affected

DCLRE1B (HGNC:17641): (DNA cross-link repair 1B) DNA interstrand cross-links prevent strand separation, thereby physically blocking transcription, replication, and segregation of DNA. DCLRE1B is one of several evolutionarily conserved genes involved in repair of interstrand cross-links (Dronkert et al., 2000 [PubMed 10848582]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCLRE1B	NM_022836.4	c.136C>T	p.Arg46Trp	missense_variant	Exon 1 of 4	ENST00000650450.2	NP_073747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLRE1B	ENST00000650450.2	c.136C>T	p.Arg46Trp	missense_variant	Exon 1 of 4		NM_022836.4	ENSP00000498042.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249188 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.136C>T (p.R46W) alteration is located in exon 1 (coding exon 1) of the DCLRE1B gene. This alteration results from a C to T substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hoyeraal-Hreidarsson syndrome;C3502105:Autosomal recessive dyskeratosis congenita Uncertain:1

Apr 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with DCLRE1B-related disease. This variant is present in population databases (rs774397708, ExAC 0.001%). This sequence change replaces arginine with tryptophan at codon 46 of the DCLRE1B protein (p.Arg46Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.0	D;.;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.026	D;.;.
Sift4G	Uncertain	0.038	D;.;.
Polyphen		1.0	D;.;D
Vest4		0.63
MutPred		0.42		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.93
MPC		0.68
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs774397708; hg19: chr1-114448344;