6-13272856-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3 BP6_Moderate BS1 BS2

The NM_030948.6(PHACTR1):c.1392-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,048 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (31 hom.)
• Consequence: PHACTR1 NM_030948.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9941
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.07

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 Benign. Variant got -9 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 6-13272856-G-A is Benign according to our data. Variant chr6-13272856-G-A is described in ClinVar as [Benign]. Clinvar id is 2656241.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00231 (3381/1461706) while in subpopulation MID AF= 0.0191 (110/5768). AF 95% confidence interval is 0.0162. There are 31 homozygotes in gnomad4_exome. There are 1981 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 347 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHACTR1	NM_030948.6	c.1392-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000332995.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHACTR1	ENST00000332995.12	c.1392-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_030948.6	P3

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 152224 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00388 AC: 968 AN: 249302 Hom.: 11 AF XY: 0.00455 AC XY: 615 AN XY: 135250

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00644

GnomAD4 exome AF: 0.00231 AC: 3381 AN: 1461706 Hom.: 31 Cov.: 30 AF XY: 0.00272 AC XY: 1981 AN XY: 727138

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152342 Hom.: 3 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74494

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00347 Hom.: 2

Bravo AF: 0.00210

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000797 AC: 3

ESP6500EA AF: 0.00292 AC: 24

ExAC AF: 0.00408 AC: 493

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00427

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

PHACTR1: BP4, BS1, BS2; TBC1D7-LOC100130357: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.020	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	0.88	D;D;D
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.22
Sift	Benign	0.084	T;D
Sift4G	Uncertain	0.028	D;D
Vest4		0.72
MVP		0.62
ClinPred		0.072	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.96
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

LitVar

Other links and lift over

dbSNP: rs185255302; hg19: chr6-13273088;