6-12749731-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_030948.6(PHACTR1):c.191G>T(p.Arg64Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R64G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 27)
• Consequence: PHACTR1 NM_030948.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-12749730-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3068777.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, PHACTR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHACTR1	NM_030948.6	c.191G>T	p.Arg64Leu	missense_variant	4/15	ENST00000332995.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHACTR1	ENST00000332995.12	c.191G>T	p.Arg64Leu	missense_variant	4/15	2	NM_030948.6	P3

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 27

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

Sep 14, 2023

The c.191G>T (p.R64L) alteration is located in exon 4 (coding exon 2) of the PHACTR1 gene. This alteration results from a G to T substitution at nucleotide position 191, causing the arginine (R) at amino acid position 64 to be replaced by a leucine (L). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.77
MutPred		0.42		Loss of MoRF binding (P = 0.0191);Loss of MoRF binding (P = 0.0191);Loss of MoRF binding (P = 0.0191);
MVP		0.59
MPC		2.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.42
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-12749963; COSMIC: COSV100277760;