NM_001083893.2:c.130C>T

Variant names:

• chr14-31026056-G-A
• rs922001430
• NM_001083893.2:c.130C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001083893.2(STRN3):​c.130C>T​(p.Pro44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,371,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: STRN3 NM_001083893.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.267
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24247324).
• BS2: High AC in GnomAdExome4 at 23 AD gene.

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.130C>T	p.Pro44Ser	missense	Exon 1 of 18	NP_001077362.1	Q13033-1
	AP4S1	NM_001128126.3	MANE Select	c.-72+269G>A		intron	N/A	NP_001121598.1	Q9Y587-1
	STRN3	NM_014574.4		c.130C>T	p.Pro44Ser	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.130C>T	p.Pro44Ser	missense	Exon 1 of 18	ENSP00000350071.5	Q13033-1
	STRN3	ENST00000355683.9	TSL:1	c.130C>T	p.Pro44Ser	missense	Exon 1 of 16	ENSP00000347909.5	Q13033-2
	AP4S1	ENST00000542754.7	TSL:1 MANE Select	c.-72+269G>A		intron	N/A	ENSP00000438170.2	Q9Y587-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000262 AC: 3 AN: 114508 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000435

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: 0.000573

GnomAD4 exome AF: 0.0000168 AC: 23 AN: 1371710 Hom.: 0 Cov.: 31 AF XY: 0.0000163 AC XY: 11 AN XY: 675854

African (AFR) AF: 0.00 AC: 0 AN: 29310

American (AMR) AF: 0.0000290 AC: 1 AN: 34462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23806

East Asian (EAS) AF: 0.0000591 AC: 2 AN: 33824

South Asian (SAS) AF: 0.00 AC: 0 AN: 77230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069146

Other (OTH) AF: 0.000351 AC: 20 AN: 56984

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

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	0.064
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.27
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.040	N
REVEL	Benign	0.17
Sift	Benign	0.21	T
Sift4G	Benign	0.57	T
Polyphen		0.017	B
Vest4		0.23
MutPred		0.22		Gain of catalytic residue at G42 (P = 5e-04)
MVP		0.88
MPC		1.5
ClinPred		0.065	T
GERP RS		1.5
PromoterAI		0.062	Neutral
Varity_R		0.060
gMVP		0.13
Mutation Taster		=98/2	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: rs922001430; hg19: chr14-31495262; COSMIC: COSV53555621; COSMIC: COSV53555621;