chr6-12749746-C-A

Variant names:

• chr6-12749746-C-A
• rs1305654074
• NM_030948.6:c.206C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030948.6(PHACTR1):​c.206C>A​(p.Thr69Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: PHACTR1 NM_030948.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51
• Publications: 0 publications found

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]

PHACTR1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 70

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000309066 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030948.6. 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
	PHACTR1	NM_030948.6	MANE Select	c.206C>A	p.Thr69Lys	missense	Exon 4 of 15	NP_112210.1	Q9C0D0-1
	PHACTR1	NM_001322310.2		c.206C>A	p.Thr69Lys	missense	Exon 2 of 14	NP_001309239.1
	PHACTR1	NM_001374581.2		c.206C>A	p.Thr69Lys	missense	Exon 3 of 13	NP_001361510.1	A0A6Q8PG87

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHACTR1	ENST00000332995.12	TSL:2 MANE Select	c.206C>A	p.Thr69Lys	missense	Exon 4 of 15	ENSP00000329880.8	Q9C0D0-1
	PHACTR1	ENST00000379348.3	TSL:1	n.383C>A		non_coding_transcript_exon	Exon 3 of 4
	PHACTR1	ENST00000674595.1		c.206C>A	p.Thr69Lys	missense	Exon 3 of 13	ENSP00000502157.1	A0A6Q8PG87

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 27

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 70 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.29
Sift	Benign	0.10	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.36		Gain of sheet (P = 0.0101)
MVP		0.71
MPC		2.3
ClinPred		0.97	D
GERP RS		4.6
PromoterAI		0.043	Neutral
Varity_R		0.38
gMVP		0.54
Mutation Taster		=44/56	disease causing

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: rs1305654074; hg19: chr6-12749978;