chr1-113904943-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 VariationId 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.

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.-99C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.-78C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_006585.2	Q9Y6B7-1
	AP4B1	NM_001437822.1		c.-78C>T		5_prime_UTR_premature_start_codon_gain	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.-78C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.-78C>T		splice_region	Exon 1 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.-78C>T		5_prime_UTR	Exon 1 of 11	ENSP00000256658.4	Q9Y6B7-1

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

African (AFR) AF: 0.580 AC: 6026 AN: 10390

American (AMR) AF: 0.181 AC: 2914 AN: 16108

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 3966 AN: 11060

East Asian (EAS) AF: 0.0974 AC: 2300 AN: 23618

South Asian (SAS) AF: 0.283 AC: 12898 AN: 45634

European-Finnish (FIN) AF: 0.247 AC: 5170 AN: 20942

Middle Eastern (MID) AF: 0.298 AC: 468 AN: 1570

European-Non Finnish (NFE) AF: 0.285 AC: 61130 AN: 214154

Other (OTH) AF: 0.294 AC: 6043 AN: 20570

GnomAD4 genome AF: 0.349 AC: 53017 AN: 151716 Hom.: 10921 Cov.: 32 AF XY: 0.342 AC XY: 25325 AN XY: 74086

African (AFR) AF: 0.572 AC: 23695 AN: 41396

American (AMR) AF: 0.221 AC: 3375 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1201 AN: 3470

East Asian (EAS) AF: 0.0750 AC: 382 AN: 5090

South Asian (SAS) AF: 0.269 AC: 1292 AN: 4806

European-Finnish (FIN) AF: 0.230 AC: 2414 AN: 10494

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19588 AN: 67882

Other (OTH) AF: 0.321 AC: 678 AN: 2110

Alfa AF: 0.304 Hom.: 21156

Bravo AF: 0.353

Asia WGS AF: 0.183 AC: 638 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.43
DANN	Benign	0.83
PhyloP100		-2.5
PromoterAI		0.027	Neutral
Mutation Taster		=297/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1217397; hg19: chr1-114447565;