20-59577527-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001199505.1(PHACTR3):c.19G>T(p.Gly7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,156,980 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 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: PHACTR3 NM_001199505.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.694

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25971).
• BS2: High AC in GnomAd at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHACTR3	NM_001199505.1	c.19G>T	p.Gly7Trp	missense_variant	1/13
PHACTR3	XM_017027628.2	c.19G>T	p.Gly7Trp	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHACTR3	ENST00000359926.7	c.19G>T	p.Gly7Trp	missense_variant	1/13	2

Frequencies

GnomAD3 genomes AF: 0.000140 AC: 21 AN: 149480 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

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: 0.00

Gnomad OTH AF: 0.000972

GnomAD4 exome AF: 0.00000596 AC: 6 AN: 1007500 Hom.: 0 Cov.: 30 AF XY: 0.00000211 AC XY: 1 AN XY: 474562

Gnomad4 AFR exome AF: 0.000197

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000523

GnomAD4 genome AF: 0.000140 AC: 21 AN: 149480 Hom.: 0 Cov.: 33 AF XY: 0.000151 AC XY: 11 AN XY: 72884

Gnomad4 AFR AF: 0.000413

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000972

Bravo AF: 0.000144

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

Oct 14, 2021

The c.19G>T (p.G7W) 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 19, causing the glycine (G) at amino acid position 7 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	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	23
Dann	Benign	0.96
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.37	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.077
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.020	D
Vest4		0.44
MutPred		0.35		Loss of methylation at R8 (P = 0.0295);
MVP		0.082
ClinPred		0.31	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: rs961562111; hg19: chr20-58152582;