20-59605025-C-T

Variant names:

• chr20-59605025-C-T
• rs979998508
• NM_080672.5:c.11C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_080672.5(PHACTR3):​c.11C>T​(p.Ser4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,338,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S4W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PHACTR3 NM_080672.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30604118).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080672.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHACTR3	NM_080672.5	MANE Select	c.11C>T	p.Ser4Leu	missense	Exon 1 of 13	NP_542403.1	Q96KR7-1
	PHACTR3	NM_001199505.1		c.109+27408C>T		intron	N/A	NP_001186434.1	Q96KR7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHACTR3	ENST00000371015.6	TSL:1 MANE Select	c.11C>T	p.Ser4Leu	missense	Exon 1 of 13	ENSP00000360054.1	Q96KR7-1
	PHACTR3	ENST00000908180.1		c.11C>T	p.Ser4Leu	missense	Exon 1 of 12	ENSP00000578239.1
	PHACTR3	ENST00000908181.1		c.11C>T	p.Ser4Leu	missense	Exon 1 of 11	ENSP00000578240.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000160 AC: 19 AN: 1186210 Hom.: 0 Cov.: 41 AF XY: 0.0000140 AC XY: 8 AN XY: 573460

African (AFR) AF: 0.00 AC: 0 AN: 24080

American (AMR) AF: 0.00 AC: 0 AN: 12874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17622

East Asian (EAS) AF: 0.00 AC: 0 AN: 27008

South Asian (SAS) AF: 0.00 AC: 0 AN: 45618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4214

European-Non Finnish (NFE) AF: 0.0000196 AC: 19 AN: 969294

Other (OTH) AF: 0.00 AC: 0 AN: 47674

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.23
MutPred		0.22		Loss of phosphorylation at S4 (P = 0.0182)
MVP		0.30
MPC		0.075
ClinPred		0.98	D
GERP RS		4.3
PromoterAI		-0.015	Neutral
Varity_R		0.36
gMVP		0.29
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs979998508; hg19: chr20-58180080;