14-31026007-G-C

Variant names:

• chr14-31026007-G-C
• rs747184947
• NM_001083893.2:c.179C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001083893.2(STRN3):​c.179C>G​(p.Pro60Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,399,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STRN3 NM_001083893.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03
• Publications: 0 publications found

Genes affected

STRN3 (HGNC:15720): (striatin 3) Enables armadillo repeat domain binding activity; protein phosphatase 2A binding activity; and small GTPase binding activity. Involved in negative regulation of transcription by RNA polymerase II and positive regulation of transcription by RNA polymerase II. Located in Golgi apparatus; nucleoplasm; and plasma membrane. Part of FAR/SIN/STRIPAK complex. [provided by Alliance of Genome Resources, Apr 2022]

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26625884).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083893.2. 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
	STRN3	NM_001083893.2	MANE Select	c.179C>G	p.Pro60Arg	missense	Exon 1 of 18	NP_001077362.1	Q13033-1
	AP4S1	NM_001128126.3	MANE Select	c.-72+220G>C		intron	N/A	NP_001121598.1	Q9Y587-1
	STRN3	NM_014574.4		c.179C>G	p.Pro60Arg	missense	Exon 1 of 16	NP_055389.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRN3	ENST00000357479.10	TSL:5 MANE Select	c.179C>G	p.Pro60Arg	missense	Exon 1 of 18	ENSP00000350071.5	Q13033-1
	STRN3	ENST00000355683.9	TSL:1	c.179C>G	p.Pro60Arg	missense	Exon 1 of 16	ENSP00000347909.5	Q13033-2
	AP4S1	ENST00000542754.7	TSL:1 MANE Select	c.-72+220G>C		intron	N/A	ENSP00000438170.2	Q9Y587-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 149884 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399666 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690960

African (AFR) AF: 0.00 AC: 0 AN: 31144

American (AMR) AF: 0.00 AC: 0 AN: 35890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.00 AC: 0 AN: 35422

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080268

Other (OTH) AF: 0.00 AC: 0 AN: 58008

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.0084	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.0
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.47	N
REVEL	Uncertain	0.44
Sift	Benign	0.35	T
Sift4G	Benign	0.58	T
Polyphen		0.92	P
Vest4		0.18
MutPred		0.36		Gain of catalytic residue at P60 (P = 0.0026)
MVP		0.89
MPC		1.6
ClinPred		0.84	D
GERP RS		4.5
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.85
Mutation Taster		=77/23	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: rs747184947; hg19: chr14-31495213;