1-113912120-A-T

Position:

• chr1-113912120-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022836.4(DCLRE1B):​c.1528A>T​(p.Asn510Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,194 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (14 hom.)
• Consequence: DCLRE1B NM_022836.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.966

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004437566).
• BP6: Variant 1-113912120-A-T is Benign according to our data. Variant chr1-113912120-A-T is described in ClinVar as [Benign]. Clinvar id is 533713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-113912120-A-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCLRE1B	NM_022836.4	c.1528A>T	p.Asn510Tyr	missense_variant	4/4	ENST00000650450.2	NP_073747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1B	ENST00000650450.2	c.1528A>T	p.Asn510Tyr	missense_variant	4/4		NM_022836.4	ENSP00000498042	P1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00196 AC: 493 AN: 251170 Hom.: 5 AF XY: 0.00227 AC XY: 309 AN XY: 135858

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00314

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00135 AC: 1977 AN: 1461880 Hom.: 14 Cov.: 31 AF XY: 0.00147 AC XY: 1071 AN XY: 727242

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000790

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74486

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00262 Hom.: 6

Bravo AF: 0.00117

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00183 AC: 222

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

- -

DCLRE1B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.63	.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N;.;.
REVEL	Benign	0.10
Sift	Uncertain	0.0050	D;.;.
Sift4G	Uncertain	0.019	D;.;.
Polyphen		0.72	P;.;P
Vest4		0.39
MVP		0.85
MPC		0.32
ClinPred		0.017	T
GERP RS		3.3
Varity_R		0.21
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35397235; hg19: chr1-114454742;