chr1-113904943-G-A

Position:

• chr1-113904943-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006594.5(AP4B1):​c.-78C>T variant causes a 5 prime UTR premature start codon gain 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. 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 NM_006594.5 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.002412
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -20 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_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
AP4B1	NM_006594.5	c.-78C>T		5_prime_UTR_premature_start_codon_gain_variant	1/11		NP_006585.2
AP4B1	NM_001253853.3	c.-247C>T		5_prime_UTR_premature_start_codon_gain_variant	1/11		NP_001240782.1
AP4B1	XM_047438847.1	c.-99C>T		5_prime_UTR_premature_start_codon_gain_variant	1/11		XP_047294803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4B1	ENST00000256658.8	c.-78C>T		5_prime_UTR_premature_start_codon_gain_variant	1/11	1		ENSP00000256658.4
AP4B1	ENST00000256658.8	c.-78C>T		splice_region_variant	1/11	1		ENSP00000256658.4
AP4B1	ENST00000256658.8	c.-78C>T		5_prime_UTR_variant	1/11	1		ENSP00000256658.4

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:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
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;