20-59577579-C-T

Variant summary

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

The NM_001199505.1(PHACTR3):c.71C>T(p.Ala24Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,208,166 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: PHACTR3 NM_001199505.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.108

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=0.016391456).
• BS2: High AC in GnomAd at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHACTR3	NM_001199505.1	c.71C>T	p.Ala24Val	missense_variant	1/13
PHACTR3	XM_017027628.2	c.71C>T	p.Ala24Val	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHACTR3	ENST00000359926.7	c.71C>T	p.Ala24Val	missense_variant	1/13	2

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 174 AN: 151448 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000961

GnomAD4 exome AF: 0.0000644 AC: 68 AN: 1056614 Hom.: 0 Cov.: 30 AF XY: 0.0000662 AC XY: 33 AN XY: 498682

Gnomad4 AFR exome AF: 0.00273

Gnomad4 AMR exome AF: 0.000266

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: 0.00000442

Gnomad4 OTH exome AF: 0.0000239

GnomAD4 genome AF: 0.00115 AC: 174 AN: 151552 Hom.: 1 Cov.: 33 AF XY: 0.00104 AC XY: 77 AN XY: 74108

Gnomad4 AFR AF: 0.00400

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000712 Hom.: 0

Bravo AF: 0.00107

ExAC AF: 0.0000459 AC: 1

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

Jun 21, 2021

The c.71C>T (p.A24V) alteration is located in exon 1 (coding exon 1) of the PHACTR3 gene. This alteration results from a C to T substitution at nucleotide position 71, causing the alanine (A) at amino acid position 24 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
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.29	N
REVEL	Benign	0.019
Sift	Benign	0.18	T
Sift4G	Benign	0.59	T
Vest4		0.13
MutPred		0.29		Loss of helix (P = 0.0558);
MVP		0.18
ClinPred		0.098	T
GERP RS		-0.47

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs529364540; hg19: chr20-58152634;