Variant 1-113904937-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The ENST00000256658.8(AP4B1):c.-77+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 533,082 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0019 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

AP4B1
ENST00000256658.8 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.9990

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.96

Variant links:

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]

AP4B1 links:

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00185 (282/152106) while in subpopulation EAS AF= 0.0491 (251/5114). AF 95% confidence interval is 0.0441. There are 12 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	Protein
AP4B1	XM_047438847.1 linkuse as main transcript	c.-93G>A	5_prime_UTR_variant	1/11	XP_047294803.1
AP4B1	NM_001253853.3 linkuse as main transcript	c.-246+5G>A	splice_donor_5th_base_variant, intron_variant		NP_001240782.1
DCLRE1B	NM_001319947.2 linkuse as main transcript	c.-331+229C>T	intron_variant		NP_001306876.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	Protein	Appris	UniProt
AP4B1	ENST00000256658.8 linkuse as main transcript	c.-77+5G>A	splice_donor_5th_base_variant, intron_variant		1	ENSP00000256658	P1	Q9Y6B7-1
AP4B1	ENST00000369571.3 linkuse as main transcript	c.-93G>A	5_prime_UTR_variant	1/11	3	ENSP00000358584	P1
AP4B1	ENST00000369564.6 linkuse as main transcript	c.-77+5G>A	splice_donor_5th_base_variant, intron_variant		5	ENSP00000358577

Frequencies

GnomAD3 genomes

AF:

0.00186

AC:

282

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0490

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00144

GnomAD4 exome

AF:

0.00243

AC:

927

AN:

380976

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

465

AN XY:

202718

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0328

Gnomad4 SAS exome

AF:

0.00108

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000266

Gnomad4 OTH exome

AF:

0.00293

GnomAD4 genome

AF:

0.00185

AC:

282

AN:

152106

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

144

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0491

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000818

Hom.:

Bravo

AF:

0.00241

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 02, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over