14-31066198-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001128126.3(AP4S1):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000137 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AP4S1 NM_001128126.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.74

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-31066198-T-C is Pathogenic according to our data. Variant chr14-31066198-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4S1	NM_001128126.3	c.2T>C	p.Met1?	start_lost	2/6	ENST00000542754.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4S1	ENST00000542754.7	c.2T>C	p.Met1?	start_lost	2/6	1	NM_001128126.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251148 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461602 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 24, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts a region of the AP4S1 protein in which other variant(s) (p.Leu6Pro) have been observed in individuals with AP4S1-related conditions (PMID: 32979048). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 520786). Disruption of the initiator codon has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects the initiator methionine of the AP4S1 mRNA. The next in-frame methionine is located at codon 7. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;.;D;D;D;.;D;D;.;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.024	D
MutationTaster	Benign	0.98	D;D;D;D;D;D
PROVEAN	Uncertain	-4.0	D;.;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;.;D
Polyphen		1.0, 0.99	.;D;D;.;.;D;.;.;.;.;D
Vest4		0.96, 0.95, 0.96, 0.94
MutPred		0.73		Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);Gain of catalytic residue at M1 (P = 0.007);
MVP		0.51
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.81
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs755820725; hg19: chr14-31535404;