6-12749703-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_030948.6(PHACTR1):c.163A>G(p.Ile55Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I55T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PHACTR1 NM_030948.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

Genes affected

PHACTR1 (HGNC:20990): (phosphatase and actin regulator 1) The protein encoded by this gene is a member of the phosphatase and actin regulator family of proteins. This family member can bind actin and regulate the reorganization of the actin cytoskeleton. It plays a role in tubule formation and in endothelial cell survival. Polymorphisms in this gene are associated with susceptibility to myocardial infarction, coronary artery disease and cervical artery dissection. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PHACTR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.086334586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHACTR1	NM_030948.6	c.163A>G	p.Ile55Val	missense_variant	4/15	ENST00000332995.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHACTR1	ENST00000332995.12	c.163A>G	p.Ile55Val	missense_variant	4/15	2	NM_030948.6	P3

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460426 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726472

Gnomad4 AFR exome AF: 0.00

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: 0.00000720

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 27

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 70 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.94
DEOGEN2	Benign	0.024	T;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.10	N
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.082
Sift	Uncertain	0.024	D;D;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.17
MutPred		0.067		Gain of MoRF binding (P = 0.1123);Gain of MoRF binding (P = 0.1123);Gain of MoRF binding (P = 0.1123);
MVP		0.25
MPC		1.1
ClinPred		0.20	T
GERP RS		4.7
Varity_R		0.078
gMVP		0.11

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: rs928863874; hg19: chr6-12749935;