rs770692934

Variant names:

• chr1-113907024-A-C
• rs770692934
• NM_022836.4:c.218A>C

Variant summary

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

The NM_022836.4(DCLRE1B):​c.218A>C​(p.Glu73Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: DCLRE1B NM_022836.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.21

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.218A>C	p.Glu73Ala	missense_variant	Exon 2 of 4	ENST00000650450.2	NP_073747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLRE1B	ENST00000650450.2	c.218A>C	p.Glu73Ala	missense_variant	Exon 2 of 4		NM_022836.4	ENSP00000498042.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151988 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251436 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151988 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jun 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with DCLRE1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 533709). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 73 of the DCLRE1B protein (p.Glu73Ala). This variant is present in population databases (rs770692934, gnomAD 0.006%). -

DCLRE1B-related disorder Uncertain:1

Apr 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DCLRE1B c.218A>C variant is predicted to result in the amino acid substitution p.Glu73Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-114449646-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	.;T;T
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.0	M;.;M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	D;.;.
REVEL	Pathogenic	0.66
Sift	Benign	0.079	T;.;.
Sift4G	Benign	0.071	T;.;.
Polyphen		0.91	P;.;P
Vest4		0.84
MutPred		0.53		Loss of solvent accessibility (P = 0.0576);Loss of solvent accessibility (P = 0.0576);Loss of solvent accessibility (P = 0.0576);
MVP		0.88
MPC		0.67
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.67
gMVP		0.75

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: rs770692934; hg19: chr1-114449646;