1-113904943-G-C

Variant names:

• chr1-113904943-G-C
• rs1217397
• ENST00000256658.8:c.-78C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006594.5(AP4B1):​c.-78C>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AP4B1 NM_006594.5 splice_region
• Scores: Splicing: ADA: 0.002627
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.49
• Publications: 37 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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_006594.5		c.-78C>G		splice_region	Exon 1 of 11	NP_006585.2	Q9Y6B7-1
	AP4B1	NM_001437822.1		c.-78C>G		splice_region	Exon 1 of 10	NP_001424751.1	B1ALD1
	AP4B1	NM_001438374.1		c.-78C>G		splice_region	Exon 1 of 9	NP_001425303.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4B1	ENST00000256658.8	TSL:1	c.-78C>G		splice_region	Exon 1 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.-78C>G		5_prime_UTR	Exon 1 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000935541.1		c.-78C>G		splice_region	Exon 1 of 11	ENSP00000605600.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 364492 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 193952

African (AFR) AF: 0.00 AC: 0 AN: 10402

American (AMR) AF: 0.00 AC: 0 AN: 16118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11074

East Asian (EAS) AF: 0.00 AC: 0 AN: 23640

South Asian (SAS) AF: 0.00 AC: 0 AN: 45644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1572

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 214454

Other (OTH) AF: 0.00 AC: 0 AN: 20604

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 21156

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.31
DANN	Benign	0.50
PhyloP100		-2.5
PromoterAI		0.046	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0026
dbscSNV1_RF	Benign	0.010
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: rs1217397; hg19: chr1-114447565;