6-12749749-C-G

Position:

• chr6-12749749-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_030948.6(PHACTR1):​c.209C>G​(p.Pro70Arg) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: PHACTR1 NM_030948.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.21

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PHACTR1. . Gene score misZ 0.708 (greater than the threshold 3.09). Trascript score misZ 3.1944 (greater than threshold 3.09). GenCC has associacion of gene with West syndrome, developmental and epileptic encephalopathy, 70.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 6-12749749-C-G is Pathogenic according to our data. Variant chr6-12749749-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2584340.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHACTR1	NM_030948.6	c.209C>G	p.Pro70Arg	missense_variant	4/15	ENST00000332995.12	NP_112210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHACTR1	ENST00000332995.12	c.209C>G	p.Pro70Arg	missense_variant	4/15	2	NM_030948.6	ENSP00000329880	P3

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 27

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 70 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Sep 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.7	N;N;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.40		Gain of MoRF binding (P = 0.0085);Gain of MoRF binding (P = 0.0085);Gain of MoRF binding (P = 0.0085);
MVP		0.75
MPC		2.4
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.46
gMVP		0.41

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: chr6-12749981;