6-13272864-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_030948.6(PHACTR1):c.1396C>A(p.Leu466Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHACTR1 NM_030948.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.75

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]

TBC1D7-LOC100130357 (HGNC:):

TBC1D7 (HGNC:21066): (TBC1 domain family member 7) This gene encodes a member of the TBC-domain containing protein family. The encoded protein functions as a subunit of the tuberous sclerosis TSC1-TSC2 complex which plays a role in the regulation of cellular growth and differentiation. Mutations in this gene have been associated with autosomal recessive megalencephaly. Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between this locus and downstream LOC100130357. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PHACTR1
• PP5: Variant 6-13272864-C-A is Pathogenic according to our data. Variant chr6-13272864-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1679588.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHACTR1	NM_030948.6	c.1396C>A	p.Leu466Met	missense_variant	11/15	ENST00000332995.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHACTR1	ENST00000332995.12	c.1396C>A	p.Leu466Met	missense_variant	11/15	2	NM_030948.6	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 70 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

May 18, 2021

The mosaic de novo c.1606C>A, p.Leu536Met missense variant identified in PHACTR1 has not been reported in the literature. This variant is not reported in thegnomAD v3.1 database, indicating a rare allele, and in silico tools predict a deleterious effect. The variant is located in the RPEL repeat domain 3 (RPEL3). Many of the pathogenic variants in PHACTR1 have been identified within one of the RPEL domains (PMID: 30256902; PMID: 23033978; PMID:28135719). RPEL repeats have been shown to be required for unpolymerised actin binding and proteins containing RPEL repeats are able to modify cell shape and/or are important in the regulation of geneexpression by the actin cytoskeleton. RPEL repeats can be found in association with the SAP motif, which could be involved in DNA binding (PMID:12732141; PMID:15620697). Based on the available evidence, the variant c.1606C>A, p.Leu536Met in the PHACTR1 gene is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Uncertain	2.8	M;M;.;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.99	D;D;.;.
Vest4		0.74
MutPred		0.58		Gain of methylation at K461 (P = 0.0748);Gain of methylation at K461 (P = 0.0748);.;.;
MVP		0.75
ClinPred		0.97	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.64

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: chr6-13273096;