ENST00000369564.6:c.-289G>C

Variant names:

• chr1-113905154-C-G
• rs1217398
• ENST00000369564.6:c.-289G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000369564.6(AP4B1):​c.-289G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 333,676 control chromosomes in the GnomAD database, including 87,921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44856 hom., cov: 33)
  • Exomes 𝑓: 0.68 (43065 hom.)
• Consequence: AP4B1 ENST00000369564.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-113905154-C-G is Benign according to our data. Variant chr1-113905154-C-G is described in ClinVar as Benign. ClinVar VariationId is 1278004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000369564.6. 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
	DCLRE1B	NM_001319947.2		c.-330-315C>G		intron	N/A	NP_001306876.1
	DCLRE1B	NM_022836.4	MANE Select	c.-433C>G		upstream_gene	N/A	NP_073747.1	Q9H816
	AP4B1	NM_001438373.1		c.-310G>C		upstream_gene	N/A	NP_001425302.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4B1	ENST00000369564.6	TSL:5	c.-289G>C		5_prime_UTR	Exon 1 of 10	ENSP00000358577.2	B1ALD1
	AP4B1	ENST00000863120.1		c.-289G>C		5_prime_UTR	Exon 1 of 9	ENSP00000533179.1
	AP4B1	ENST00000935537.1		c.-289G>C		5_prime_UTR	Exon 1 of 9	ENSP00000605596.1

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115388 AN: 152066 Hom.: 44802 Cov.: 33

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.734

GnomAD4 exome AF: 0.682 AC: 123707 AN: 181492 Hom.: 43065 Cov.: 0 AF XY: 0.669 AC XY: 65051 AN XY: 97190

African (AFR) AF: 0.943 AC: 5192 AN: 5504

American (AMR) AF: 0.699 AC: 4729 AN: 6762

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 3218 AN: 4726

East Asian (EAS) AF: 0.843 AC: 6275 AN: 7446

South Asian (SAS) AF: 0.580 AC: 18273 AN: 31524

European-Finnish (FIN) AF: 0.707 AC: 6420 AN: 9082

Middle Eastern (MID) AF: 0.641 AC: 441 AN: 688

European-Non Finnish (NFE) AF: 0.682 AC: 72540 AN: 106328

Other (OTH) AF: 0.702 AC: 6619 AN: 9432

GnomAD4 genome AF: 0.759 AC: 115498 AN: 152184 Hom.: 44856 Cov.: 33 AF XY: 0.757 AC XY: 56314 AN XY: 74364

African (AFR) AF: 0.935 AC: 38841 AN: 41556

American (AMR) AF: 0.727 AC: 11129 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 2365 AN: 3470

East Asian (EAS) AF: 0.853 AC: 4387 AN: 5144

South Asian (SAS) AF: 0.572 AC: 2756 AN: 4816

European-Finnish (FIN) AF: 0.701 AC: 7422 AN: 10588

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.680 AC: 46233 AN: 67988

Other (OTH) AF: 0.734 AC: 1553 AN: 2116

Alfa AF: 0.665 Hom.: 2234

Bravo AF: 0.771

Asia WGS AF: 0.713 AC: 2480 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.47
PhyloP100		1.1
PromoterAI		0.034	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1217398; hg19: chr1-114447776;