14-31025782-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001128126.3(AP4S1):c.-77G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 1,365,960 control chromosomes in the GnomAD database, including 2,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (351 hom., cov: 31)
  • Exomes 𝑓: 0.046 (2121 hom.)
• Consequence: AP4S1 NM_001128126.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.150

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 14-31025782-G-A is Benign according to our data. Variant chr14-31025782-G-A is described in ClinVar as [Benign]. Clinvar id is 380897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4S1	NM_001128126.3	c.-77G>A		5_prime_UTR_variant	1/6	ENST00000542754.7
STRN3	NM_001083893.2	c.282+122C>T		intron_variant		ENST00000357479.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4S1	ENST00000542754.7	c.-77G>A		5_prime_UTR_variant	1/6	1	NM_001128126.3	P1
STRN3	ENST00000357479.10	c.282+122C>T		intron_variant		5	NM_001083893.2	P3

Frequencies

GnomAD3 genomes AF: 0.0523 AC: 7952 AN: 152170 Hom.: 343 Cov.: 31

Gnomad AFR AF: 0.0438

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0645

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.0700

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0322

Gnomad OTH AF: 0.0478

GnomAD4 exome AF: 0.0458 AC: 55638 AN: 1213672 Hom.: 2121 Cov.: 17 AF XY: 0.0461 AC XY: 27669 AN XY: 600732

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.0668

Gnomad4 EAS exome AF: 0.211

Gnomad4 SAS exome AF: 0.0712

Gnomad4 FIN exome AF: 0.0451

Gnomad4 NFE exome AF: 0.0343

Gnomad4 OTH exome AF: 0.0536

GnomAD4 genome AF: 0.0524 AC: 7974 AN: 152288 Hom.: 351 Cov.: 31 AF XY: 0.0549 AC XY: 4085 AN XY: 74464

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0645

Gnomad4 EAS AF: 0.213

Gnomad4 SAS AF: 0.0702

Gnomad4 FIN AF: 0.0533

Gnomad4 NFE AF: 0.0322

Gnomad4 OTH AF: 0.0543

Alfa AF: 0.0428 Hom.: 50

Bravo AF: 0.0577

Asia WGS AF: 0.154 AC: 532 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.2
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78648016; hg19: chr14-31494988;