rs28364563

Variant names:

• chr1-113904937-C-T
• rs28364563
• ENST00000256658.8:c.-77+5G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_006594.5(AP4B1):​c.-77+5G>A variant causes a splice region, 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 NM_006594.5 splice_region, intron
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.96
• Publications: 3 publications found

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]

DCLRE1B Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal recessive 8

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006594.5. 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
	AP4B1	NM_001438373.1		c.-93G>A		5_prime_UTR	Exon 1 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.-77+5G>A		splice_region intron	N/A	NP_006585.2	Q9Y6B7-1
	AP4B1	NM_001437822.1		c.-77+5G>A		splice_region intron	N/A	NP_001424751.1	B1ALD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4B1	ENST00000256658.8	TSL:1	c.-77+5G>A		splice_region intron	N/A	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000863127.1		c.-220G>A		5_prime_UTR	Exon 1 of 11	ENSP00000533186.1
	AP4B1	ENST00000369571.3	TSL:3	c.-93G>A		5_prime_UTR	Exon 1 of 11	ENSP00000358584.3	Q9Y6B7-1

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 282 AN: 151986 Hom.: 12 Cov.: 33

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.: 9 Cov.: 3 AF XY: 0.00229 AC XY: 465 AN XY: 202718

African (AFR) AF: 0.00 AC: 0 AN: 10964

American (AMR) AF: 0.00 AC: 0 AN: 16806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11700

East Asian (EAS) AF: 0.0328 AC: 808 AN: 24650

South Asian (SAS) AF: 0.00108 AC: 50 AN: 46338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1666

European-Non Finnish (NFE) AF: 0.0000266 AC: 6 AN: 225226

Other (OTH) AF: 0.00293 AC: 63 AN: 21496

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152106 Hom.: 12 Cov.: 33 AF XY: 0.00194 AC XY: 144 AN XY: 74346

African (AFR) AF: 0.000313 AC: 13 AN: 41524

American (AMR) AF: 0.000523 AC: 8 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0491 AC: 251 AN: 5114

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67958

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000677 Hom.: 0

Bravo AF: 0.00241

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.85
PhyloP100		2.0
PromoterAI		-0.11	Neutral
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs28364563; hg19: chr1-114447559;