chr14-31025981-G-C

Variant names:

• chr14-31025981-G-C
• rs772072359
• NM_001083893.2:c.205C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001083893.2(STRN3):​c.205C>G​(p.Leu69Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,422,538 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STRN3 NM_001083893.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.205C>G	p.Leu69Val	missense	Exon 1 of 18	NP_001077362.1	Q13033-1
	AP4S1	NM_001128126.3	MANE Select	c.-72+194G>C		intron	N/A	NP_001121598.1	Q9Y587-1
	STRN3	NM_014574.4		c.205C>G	p.Leu69Val	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.205C>G	p.Leu69Val	missense	Exon 1 of 18	ENSP00000350071.5	Q13033-1
	STRN3	ENST00000355683.9	TSL:1	c.205C>G	p.Leu69Val	missense	Exon 1 of 16	ENSP00000347909.5	Q13033-2
	AP4S1	ENST00000542754.7	TSL:1 MANE Select	c.-72+194G>C		intron	N/A	ENSP00000438170.2	Q9Y587-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1422538 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704486

African (AFR) AF: 0.0000311 AC: 1 AN: 32154

American (AMR) AF: 0.00 AC: 0 AN: 38562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25456

East Asian (EAS) AF: 0.00 AC: 0 AN: 36806

South Asian (SAS) AF: 0.00 AC: 0 AN: 81448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1093254

Other (OTH) AF: 0.00 AC: 0 AN: 58882

GnomAD4 genome Cov.: 31

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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.58	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.4
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.65		Gain of catalytic residue at L69 (P = 0.0056)
MVP		0.88
MPC		2.8
ClinPred		0.98	D
GERP RS		2.8
PromoterAI		-0.026	Neutral
Varity_R		0.68
gMVP		0.75
Mutation Taster		=52/48	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: rs772072359; hg19: chr14-31495187;