1-113904943-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000256658.8(AP4B1):c.-78C>T variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 515,762 control chromosomes in the GnomAD database, including 26,127 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10921 hom., cov: 32)
  • Exomes 𝑓: 0.28 (15206 hom.)
• Consequence: AP4B1 ENST00000256658.8 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.002412
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.49

Genes affected

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]

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-113904943-G-A is Benign according to our data. Variant chr1-113904943-G-A is described in ClinVar as [Benign]. Clinvar id is 380767.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4B1	NM_001253853.3	c.-247C>T		splice_region_variant, 5_prime_UTR_variant	1/11
AP4B1	NM_006594.5	c.-78C>T		splice_region_variant, 5_prime_UTR_variant	1/11
AP4B1	XM_011540523.4	c.-78C>T		splice_region_variant, 5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4B1	ENST00000256658.8	c.-78C>T		splice_region_variant, 5_prime_UTR_variant	1/11	1		P1
AP4B1	ENST00000369564.6	c.-78C>T		splice_region_variant, 5_prime_UTR_variant	1/10	5
AP4B1	ENST00000369571.3	c.-99C>T		5_prime_UTR_variant	1/11	3		P1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52960 AN: 151598 Hom.: 10902 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.0749

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.324

GnomAD4 exome AF: 0.277 AC: 100915 AN: 364046 Hom.: 15206 Cov.: 3 AF XY: 0.277 AC XY: 53636 AN XY: 193724

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.359

Gnomad4 EAS exome AF: 0.0974

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.247

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.349 AC: 53017 AN: 151716 Hom.: 10921 Cov.: 32 AF XY: 0.342 AC XY: 25325 AN XY: 74086

Gnomad4 AFR AF: 0.572

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.346

Gnomad4 EAS AF: 0.0750

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.230

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.321

Alfa AF: 0.289 Hom.: 12467

Bravo AF: 0.353

Asia WGS AF: 0.183 AC: 638 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.43
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.012
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: rs1217397; hg19: chr1-114447565;