rs139767046

Variant names:

• chr14-31065881-C-T
• rs139767046
• NM_001128126.3:c.-71-245C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001128126.3(AP4S1):​c.-71-245C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 152,108 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0038 (7 hom., cov: 33)
• Consequence: AP4S1 NM_001128126.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.198
• Publications: 1 publications found

Genes affected

AP4S1 (HGNC:575): (adaptor related protein complex 4 subunit sigma 1) This gene encodes a member of the adaptor complexes small subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]

AP4S1 Gene-Disease associations (from GenCC):

• AP-4 deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 52

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• AP4-related intellectual disability and spastic paraplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-31065881-C-T is Benign according to our data. Variant chr14-31065881-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1194941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00377 (574/152108) while in subpopulation AFR AF = 0.0127 (526/41478). AF 95% confidence interval is 0.0118. There are 7 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128126.3. 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
	AP4S1	NM_001128126.3	MANE Select	c.-71-245C>T		intron	N/A	NP_001121598.1	Q9Y587-1
	AP4S1	NM_007077.5		c.-71-245C>T		intron	N/A	NP_009008.2
	AP4S1	NM_001254727.2		c.-71-245C>T		intron	N/A	NP_001241656.1	Q9Y587-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4S1	ENST00000542754.7	TSL:1 MANE Select	c.-71-245C>T		intron	N/A	ENSP00000438170.2	Q9Y587-1
	AP4S1	ENST00000334725.8	TSL:1	c.-71-245C>T		intron	N/A	ENSP00000334484.4	Q9Y587-4
	AP4S1	ENST00000313566.11	TSL:3	c.-71-245C>T		intron	N/A	ENSP00000322508.8	A0A8C8KCP6

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 151990 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00336

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152108 Hom.: 7 Cov.: 33 AF XY: 0.00359 AC XY: 267 AN XY: 74364

African (AFR) AF: 0.0127 AC: 526 AN: 41478

American (AMR) AF: 0.00190 AC: 29 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67996

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00355 Hom.: 0

Bravo AF: 0.00452

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.87
CADD	Benign	4.2
DANN	Benign	0.88
PhyloP100		-0.20
PromoterAI		-0.0070	Neutral
Mutation Taster		=100/0	polymorphism

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: rs139767046; hg19: chr14-31535087;