1-113904989-T-C

Variant names:

• chr1-113904989-T-C
• rs189306022
• ENST00000256658.8:c.-124A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_006594.5(AP4B1):​c.-124A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 458,258 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (25 hom.)
• Consequence: AP4B1 NM_006594.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.591
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 1-113904989-T-C is Benign according to our data. Variant chr1-113904989-T-C is described in ClinVar as Benign. ClinVar VariationId is 1271892.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00833 (1267/152106) while in subpopulation NFE AF = 0.0083 (564/67982). AF 95% confidence interval is 0.00773. There are 22 homozygotes in GnomAd4. There are 748 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.-145A>G		5_prime_UTR	Exon 1 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.-124A>G		5_prime_UTR	Exon 1 of 11	NP_006585.2	Q9Y6B7-1
	AP4B1	NM_001437822.1		c.-124A>G		5_prime_UTR	Exon 1 of 10	NP_001424751.1	B1ALD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4B1	ENST00000256658.8	TSL:1	c.-124A>G		5_prime_UTR	Exon 1 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000369571.3	TSL:3	c.-145A>G		5_prime_UTR	Exon 1 of 11	ENSP00000358584.3	Q9Y6B7-1
	AP4B1	ENST00000369564.6	TSL:5	c.-124A>G		5_prime_UTR	Exon 1 of 10	ENSP00000358577.2	B1ALD1

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1267 AN: 151988 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00830

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00745 AC: 2281 AN: 306152 Hom.: 25 Cov.: 0 AF XY: 0.00681 AC XY: 1113 AN XY: 163502

African (AFR) AF: 0.00102 AC: 9 AN: 8866

American (AMR) AF: 0.00257 AC: 36 AN: 14008

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 23 AN: 8850

East Asian (EAS) AF: 0.0000552 AC: 1 AN: 18108

South Asian (SAS) AF: 0.000889 AC: 39 AN: 43868

European-Finnish (FIN) AF: 0.0486 AC: 762 AN: 15666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1214

European-Non Finnish (NFE) AF: 0.00728 AC: 1301 AN: 178666

Other (OTH) AF: 0.00651 AC: 110 AN: 16906

GnomAD4 genome AF: 0.00833 AC: 1267 AN: 152106 Hom.: 22 Cov.: 33 AF XY: 0.0101 AC XY: 748 AN XY: 74366

African (AFR) AF: 0.000650 AC: 27 AN: 41508

American (AMR) AF: 0.00268 AC: 41 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0566 AC: 599 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00830 AC: 564 AN: 67982

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.0133 Hom.: 8

Bravo AF: 0.00342

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.5
DANN	Benign	0.38
PhyloP100		0.59
PromoterAI		0.043	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs189306022; hg19: chr1-114447611;