rs755820725

Variant names:

• chr14-31066198-T-A
• rs755820725
• NM_001128126.3:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-31066198-T-A
• chr14-31066198-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PS1_Moderate PM2

The NM_001128126.3(AP4S1):​c.2T>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000205 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AP4S1 NM_001128126.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 7 codons. Genomic position: 31066215. Lost 0.044 part of the original CDS.
• PS1: Another start lost variant in NM_001128126.3 (AP4S1) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4S1	NM_001128126.3	c.2T>A	p.Met1?	start_lost	Exon 2 of 6	ENST00000542754.7	NP_001121598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4S1	ENST00000542754.7	c.2T>A	p.Met1?	start_lost	Exon 2 of 6	1	NM_001128126.3	ENSP00000438170.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251148 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461602 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;D;D;.;T;.;.;D;.;.;D
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	0.014	T
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.024	D
PhyloP100		6.7
PROVEAN	Pathogenic	-4.6	D;.;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.54
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, 0.93, 0.93, 0.93, 0.95, 0.91
MutPred		0.74		Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);
MVP		0.51
ClinPred		0.94	D
GERP RS		6.0
PromoterAI		0.018	Neutral
Varity_R		0.93
gMVP		0.80
Mutation Taster		=26/174	disease causing

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: rs755820725; hg19: chr14-31535404;