NM_022836.4:c.181C>T

Variant names:

• chr1-113905767-C-T
• rs11552449
• NM_022836.4:c.181C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.69
• Publications: 120 publications found

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]

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

ACMG classification

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	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	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.: 32

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

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.: 32 AF XY: 0.183 AC XY: 132809 AN XY: 726224

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

GnomAD4 genome AF: 0.161 AC: 24493 AN: 152194 Hom.: 2950 Cov.: 32 AF XY: 0.166 AC XY: 12320 AN XY: 74394

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: 50 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11544 AN: 68000

Other (OTH) AF: 0.178 AC: 375 AN: 2112

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

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	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.062	T;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.66	.;T;T
MetaRNN	Benign	0.00024	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N
PhyloP100		3.7
PrimateAI	Benign	0.32	T
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	T
GERP RS		3.6
PromoterAI		-0.026	Neutral
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)

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: rs11552449; hg19: chr1-114448389; COSMIC: COSV56724332; COSMIC: COSV56724332;