chr6-13053389-C-T

Variant names:

• chr6-13053389-C-T
• rs767982489
• NM_030948.6:c.275C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_030948.6(PHACTR1):​c.275C>T​(p.Ala92Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000823 in 1,457,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PHACTR1 NM_030948.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.01
• Publications: 1 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39720157).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

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.275C>T	p.Ala92Val	missense	Exon 5 of 15	NP_112210.1	Q9C0D0-1
	PHACTR1	NM_001322314.4		c.278C>T	p.Ala93Val	missense	Exon 2 of 13	NP_001309243.1	A0A6Q8PGC2
	PHACTR1	NM_001322310.2		c.275C>T	p.Ala92Val	missense	Exon 3 of 14	NP_001309239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHACTR1	ENST00000332995.12	TSL:2 MANE Select	c.275C>T	p.Ala92Val	missense	Exon 5 of 15	ENSP00000329880.8	Q9C0D0-1
	PHACTR1	ENST00000675203.2		c.278C>T	p.Ala93Val	missense	Exon 2 of 13	ENSP00000502172.2	A0A6Q8PGC2
	PHACTR1	ENST00000674595.1		c.275C>T	p.Ala92Val	missense	Exon 4 of 13	ENSP00000502157.1	A0A6Q8PG87

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000824 AC: 2 AN: 242824 AF XY: 0.00000757

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1457528 Hom.: 0 Cov.: 30 AF XY: 0.00000966 AC XY: 7 AN XY: 724762

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.0000227 AC: 1 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39478

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52952

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109956

Other (OTH) AF: 0.0000166 AC: 1 AN: 60174

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Developmental and epileptic encephalopathy, 70 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N
PhyloP100		5.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.18
Sift	Benign	0.16	T
Sift4G	Benign	0.46	T
Polyphen		0.99	D
Vest4		0.40
MutPred		0.26		Loss of disorder (P = 0.07)
MVP		0.40
ClinPred		0.66	D
GERP RS		5.8
PromoterAI		-0.019	Neutral
Varity_R		0.090
gMVP		0.35
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs767982489; hg19: chr6-13053621; COSMIC: COSV60674729; COSMIC: COSV60674729;