1-113905767-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022836.4(DCLRE1B):c.181C>T(p.His61Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.183 in 1,612,434 control chromosomes in the GnomAD database, including 33,388 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2950 hom., cov: 32)

Exomes 𝑓: 0.19 ( 30438 hom. )

Consequence

DCLRE1B
NM_022836.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.69

Publications

120 publications found

Variant links:

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]

DCLRE1B links:

AP4B1 (HGNC:572): (adaptor related protein complex 4 subunit beta 1) This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

AP4B1 Gene-Disease associations (from GenCC):

AP-4 deficiency syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 47
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
AP4-related intellectual disability and spastic paraplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AP4B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.374649E-4).

BP6

Variant 1-113905767-C-T is Benign according to our data. Variant chr1-113905767-C-T is described in ClinVar as Benign. ClinVar VariationId is 225770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCLRE1B	NM_022836.4 link	c.181C>T	p.His61Tyr	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 link	c.181C>T	p.His61Tyr	missense_variant	Exon 1 of 4		NM_022836.4	ENSP00000498042.1

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24503

AN:

152076

Hom.:

2957

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0390

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.310

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.584

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.179

GnomAD2 exomes

AF:

0.223

AC:

55284

AN:

247452

AF XY:

0.212

show subpopulations

Gnomad AFR exome

AF:

0.0347

Gnomad AMR exome

AF:

0.433

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.592

Gnomad FIN exome

AF:

0.182

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.193

GnomAD4 exome

AF:

0.185

AC:

270551

AN:

1460240

Hom.:

30438

Cov.:

AF XY:

0.183

AC XY:

132809

AN XY:

726224

show subpopulations

African (AFR)

AF:

0.0340

AC:

1138

AN:

33456

American (AMR)

AF:

0.419

AC:

18674

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

3152

AN:

26074

East Asian (EAS)

AF:

0.561

AC:

22233

AN:

39628

South Asian (SAS)

AF:

0.138

AC:

11906

AN:

86048

European-Finnish (FIN)

AF:

0.185

AC:

9854

AN:

53372

Middle Eastern (MID)

AF:

0.173

AC:

997

AN:

5754

European-Non Finnish (NFE)

AF:

0.172

AC:

191344

AN:

1111062

Other (OTH)

AF:

0.187

AC:

11253

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

11025

22050

33074

44099

55124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7028

14056

21084

28112

35140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.161

AC:

24493

AN:

152194

Hom.:

2950

Cov.:

AF XY:

0.166

AC XY:

12320

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0390

AC:

1619

AN:

41560

American (AMR)

AF:

0.310

AC:

4730

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

405

AN:

3472

East Asian (EAS)

AF:

0.583

AC:

3002

AN:

5152

South Asian (SAS)

AF:

0.154

AC:

745

AN:

4830

European-Finnish (FIN)

AF:

0.182

AC:

1928

AN:

10590

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.170

AC:

11544

AN:

68000

Other (OTH)

AF:

0.178

AC:

375

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

947

1894

2842

3789

4736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.175

Hom.:

7961

Bravo

AF:

0.172

TwinsUK

AF:

0.173

AC:

641

ALSPAC

AF:

0.175

AC:

675

ESP6500AA

AF:

0.0420

AC:

185

ESP6500EA

AF:

0.174

AC:

1495

ExAC

AF:

0.211

AC:

25585

Asia WGS

AF:

0.317

AC:

1101

AN:

3478

EpiCase

AF:

0.160

EpiControl

AF:

0.163

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 62% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Hereditary spastic paraplegia 47

Benign:1

Nov 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hoyeraal-Hreidarsson syndrome;C3502105:Autosomal recessive dyskeratosis congenita

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.062

T;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.66

.;T;T

MetaRNN

Benign

0.00024

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;N

PhyloP100

3.7

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.61

N;.;.

REVEL

Benign

0.17

Sift

Benign

0.49

T;.;.

Sift4G

Benign

0.15

T;.;.

Polyphen

0.14

B;.;B

Vest4

0.047

MPC

0.20

ClinPred

0.018

GERP RS

3.6

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.092

gMVP

0.63

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over