20-59577524-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001199505.1(PHACTR3):c.16G>T(p.Gly6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,149,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PHACTR3 NM_001199505.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

Genes affected

PHACTR3 (HGNC:15833): (phosphatase and actin regulator 3) This gene encodes a member of the phosphatase and actin regulator protein family. The encoded protein is associated with the nuclear scaffold in proliferating cells, and binds to actin and the catalytic subunit of protein phosphatase-1, suggesting that it functions as a regulatory subunit of protein phosphatase-1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06714946).
• BS2: High AC in GnomAd at 234 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHACTR3	NM_001199505.1	c.16G>T	p.Gly6Trp	missense_variant	1/13
PHACTR3	XM_017027628.2	c.16G>T	p.Gly6Trp	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHACTR3	ENST00000359926.7	c.16G>T	p.Gly6Trp	missense_variant	1/13	2

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 234 AN: 149352 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000533

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 110 AN: 999836 Hom.: 0 Cov.: 30 AF XY: 0.000119 AC XY: 56 AN XY: 470790

Gnomad4 AFR exome AF: 0.00429

Gnomad4 AMR exome AF: 0.000177

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000212

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000230

Gnomad4 OTH exome AF: 0.000450

GnomAD4 genome AF: 0.00157 AC: 234 AN: 149460 Hom.: 0 Cov.: 33 AF XY: 0.00156 AC XY: 114 AN XY: 72928

Gnomad4 AFR AF: 0.00528

Gnomad4 AMR AF: 0.000532

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000149

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000143 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.16G>T (p.G6W) alteration is located in exon 1 (coding exon 1) of the PHACTR3 gene. This alteration results from a G to T substitution at nucleotide position 16, causing the glycine (G) at amino acid position 6 to be replaced by a tryptophan (W). 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
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Benign	0.94
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.070	N
REVEL	Benign	0.066
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.047	D
Vest4		0.42
MutPred		0.36		Loss of methylation at R2 (P = 0.0388);
MVP		0.068
ClinPred		0.36	T
GERP RS		1.5

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs865912633; hg19: chr20-58152579;