chr14-31026088-C-T

Variant names:

• chr14-31026088-C-T
• rs1378637885
• NM_001083893.2:c.98G>A

Variant summary

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

The NM_001083893.2(STRN3):​c.98G>A​(p.Gly33Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,376,936 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: 7.3e-7 (0 hom.)
• Consequence: STRN3 NM_001083893.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• 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=0.28454822).

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.98G>A	p.Gly33Glu	missense	Exon 1 of 18	NP_001077362.1	Q13033-1
	AP4S1	NM_001128126.3	MANE Select	c.-72+301C>T		intron	N/A	NP_001121598.1	Q9Y587-1
	STRN3	NM_014574.4		c.98G>A	p.Gly33Glu	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.98G>A	p.Gly33Glu	missense	Exon 1 of 18	ENSP00000350071.5	Q13033-1
	STRN3	ENST00000355683.9	TSL:1	c.98G>A	p.Gly33Glu	missense	Exon 1 of 16	ENSP00000347909.5	Q13033-2
	AP4S1	ENST00000542754.7	TSL:1 MANE Select	c.-72+301C>T		intron	N/A	ENSP00000438170.2	Q9Y587-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1376936 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 678780

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28890

American (AMR) AF: 0.00 AC: 0 AN: 34362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24174

East Asian (EAS) AF: 0.00 AC: 0 AN: 33498

South Asian (SAS) AF: 0.00 AC: 0 AN: 78064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45482

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

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070762

Other (OTH) AF: 0.00 AC: 0 AN: 57062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	Benign	0.21
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.13
Sift	Uncertain	0.019	D
Sift4G	Benign	0.10	T
Polyphen		0.058	B
Vest4		0.48
MutPred		0.24		Gain of catalytic residue at L30 (P = 2e-04)
MVP		0.79
MPC		1.8
ClinPred		0.65	D
GERP RS		3.8
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.089
gMVP		0.72
Mutation Taster		=93/7	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: rs1378637885; hg19: chr14-31495294;