14-31025981-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRN3	NM_001083893.2	c.205C>G	p.Leu69Val	missense_variant	Exon 1 of 18	ENST00000357479.10	NP_001077362.1
AP4S1	NM_001128126.3	c.-72+194G>C		intron_variant	Intron 1 of 5	ENST00000542754.7	NP_001121598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRN3	ENST00000357479.10	c.205C>G	p.Leu69Val	missense_variant	Exon 1 of 18	5	NM_001083893.2	ENSP00000350071.5
AP4S1	ENST00000542754.7	c.-72+194G>C		intron_variant	Intron 1 of 5	1	NM_001128126.3	ENSP00000438170.2

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

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.205C>G (p.L69V) alteration is located in exon 1 (coding exon 1) of the STRN3 gene. This alteration results from a C to G substitution at nucleotide position 205, causing the leucine (L) at amino acid position 69 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;B
Vest4		0.38
MutPred		0.65		Gain of catalytic residue at L69 (P = 0.0056);Gain of catalytic residue at L69 (P = 0.0056);
MVP		0.88
MPC		2.8
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.68
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-31495187;