chr1-113905292-G-T

Variant names:

• chr1-113905292-G-T
• rs971173
• ENST00000650596.1:c.-295G>T

Variant summary

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

The NM_001319947.2(DCLRE1B):​c.-330-177G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 406,054 control chromosomes in the GnomAD database, including 29,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (15496 hom., cov: 33)
  • Exomes 𝑓: 0.31 (13763 hom.)
• Consequence: DCLRE1B NM_001319947.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08
• Publications: 16 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.69).
• BP6: Variant 1-113905292-G-T is Benign according to our data. Variant chr1-113905292-G-T is described in ClinVar as Benign. ClinVar VariationId is 1259443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319947.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1B	NM_001319947.2		c.-330-177G>T		intron	N/A	NP_001306876.1
	DCLRE1B	NM_022836.4	MANE Select	c.-295G>T		upstream_gene	N/A	NP_073747.1	Q9H816
	DCLRE1B	NM_001363690.2		c.-295G>T		upstream_gene	N/A	NP_001350619.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1B	ENST00000650596.1		c.-295G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000497882.1	A0A3B3ITQ0
	AP4B1	ENST00000935535.1		c.-142C>A		5_prime_UTR	Exon 1 of 11	ENSP00000605594.1
	DCLRE1B	ENST00000650596.1		c.-295G>T		5_prime_UTR	Exon 1 of 3	ENSP00000497882.1	A0A3B3ITQ0

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61852 AN: 151910 Hom.: 15466 Cov.: 33

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.310 AC: 78818 AN: 254026 Hom.: 13763 Cov.: 2 AF XY: 0.309 AC XY: 40941 AN XY: 132406

African (AFR) AF: 0.707 AC: 4858 AN: 6876

American (AMR) AF: 0.213 AC: 1642 AN: 7700

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 3360 AN: 8260

East Asian (EAS) AF: 0.0965 AC: 1406 AN: 14572

South Asian (SAS) AF: 0.321 AC: 9178 AN: 28608

European-Finnish (FIN) AF: 0.265 AC: 4186 AN: 15792

Middle Eastern (MID) AF: 0.350 AC: 425 AN: 1214

European-Non Finnish (NFE) AF: 0.312 AC: 48699 AN: 155882

Other (OTH) AF: 0.335 AC: 5064 AN: 15122

GnomAD4 genome AF: 0.407 AC: 61932 AN: 152028 Hom.: 15496 Cov.: 33 AF XY: 0.399 AC XY: 29642 AN XY: 74300

African (AFR) AF: 0.705 AC: 29245 AN: 41498

American (AMR) AF: 0.258 AC: 3937 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1386 AN: 3472

East Asian (EAS) AF: 0.0757 AC: 390 AN: 5150

South Asian (SAS) AF: 0.301 AC: 1451 AN: 4826

European-Finnish (FIN) AF: 0.258 AC: 2721 AN: 10558

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21603 AN: 67926

Other (OTH) AF: 0.375 AC: 790 AN: 2106

Alfa AF: 0.350 Hom.: 6626

Bravo AF: 0.414

Asia WGS AF: 0.214 AC: 746 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		1.1
PromoterAI		-0.16	Neutral
Mutation Taster		=300/0	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: rs971173; hg19: chr1-114447914; COSMIC: COSV56724812; COSMIC: COSV56724812;