20-59767334-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_080672.5(PHACTR3):c.690C>A(p.Ser230Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,614,010 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: 𝑓 0.00020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PHACTR3 NM_080672.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity PHAR3_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.1039058).
• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHACTR3	NM_080672.5	c.690C>A	p.Ser230Arg	missense_variant	5/13	ENST00000371015.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHACTR3	ENST00000371015.6	c.690C>A	p.Ser230Arg	missense_variant	5/13	1	NM_080672.5	A1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152190 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 250782 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135758

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000233 AC: 340 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.000241 AC XY: 175 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152190 Hom.: 0 Cov.: 34 AF XY: 0.000242 AC XY: 18 AN XY: 74362

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000212

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

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 02, 2021

The c.690C>A (p.S230R) alteration is located in exon 5 (coding exon 5) of the PHACTR3 gene. This alteration results from a C to A substitution at nucleotide position 690, causing the serine (S) at amino acid position 230 to be replaced by an arginine (R). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D;.;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.034	D;D;D;D;D
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.56	.;P;.;.;.
Vest4		0.49
MutPred		0.32		.;Gain of solvent accessibility (P = 6e-04);.;.;.;
MVP		0.32
MPC		0.44
ClinPred		0.22	T
GERP RS		2.8
Varity_R		0.14
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs201118563; hg19: chr20-58342389;