6-13286236-GTT-GTTT

Variant names:

• chr6-13286236-G-GT
• rs750206884
• NM_030948.6:c.1727+24dupT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PVS1_Moderate BP6_Moderate BS2

The NM_001374581.2(PHACTR1):​c.1751dupT​(p.Leu585ProfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,370,204 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.012 (1 hom.)
• Consequence: PHACTR1 NM_001374581.2 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.588
• 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]

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]

TBC1D7 Gene-Disease associations (from GenCC):

• macrocephaly/megalencephaly syndrome, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0218 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 6-13286236-G-GT is Benign according to our data. Variant chr6-13286236-G-GT is described in ClinVar as Likely_benign. ClinVar VariationId is 3024709.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 278 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374581.2. 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.1727+24dupT		intron	N/A	NP_112210.1	Q9C0D0-1
	PHACTR1	NM_001374581.2		c.1751dupT	p.Leu585ProfsTer45	frameshift	Exon 13 of 13	NP_001361510.1	A0A6Q8PG87
	PHACTR1	NM_001374583.2		c.1475dupT	p.Leu493ProfsTer45	frameshift	Exon 11 of 11	NP_001361512.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHACTR1	ENST00000332995.12	TSL:2 MANE Select	c.1727+24dupT		intron	N/A	ENSP00000329880.8	Q9C0D0-1
	PHACTR1	ENST00000674595.1		c.1751dupT	p.Leu585ProfsTer45	frameshift	Exon 13 of 13	ENSP00000502157.1	A0A6Q8PG87
	PHACTR1	ENST00000675203.2		c.1937+24dupT		intron	N/A	ENSP00000502172.2	A0A6Q8PGC2

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 279 AN: 148780 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00437

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.00570

Gnomad SAS AF: 0.00171

Gnomad FIN AF: 0.000300

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00167

Gnomad OTH AF: 0.00393

GnomAD2 exomes AF: 0.0200 AC: 2211 AN: 110754 AF XY: 0.0202

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.0307

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.0315

Gnomad FIN exome AF: 0.00634

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0122 AC: 14877 AN: 1221312 Hom.: 1 Cov.: 29 AF XY: 0.0124 AC XY: 7465 AN XY: 602202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0114 AC: 304 AN: 26654

American (AMR) AF: 0.0168 AC: 432 AN: 25712

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 262 AN: 20272

East Asian (EAS) AF: 0.0152 AC: 497 AN: 32602

South Asian (SAS) AF: 0.0151 AC: 942 AN: 62502

European-Finnish (FIN) AF: 0.00691 AC: 305 AN: 44148

Middle Eastern (MID) AF: 0.00709 AC: 35 AN: 4940

European-Non Finnish (NFE) AF: 0.0120 AC: 11474 AN: 954604

Other (OTH) AF: 0.0126 AC: 626 AN: 49878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00187 AC: 278 AN: 148892 Hom.: 1 Cov.: 32 AF XY: 0.00180 AC XY: 131 AN XY: 72616

African (AFR) AF: 0.00118 AC: 48 AN: 40612

American (AMR) AF: 0.00437 AC: 65 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 4 AN: 3418

East Asian (EAS) AF: 0.00552 AC: 28 AN: 5076

South Asian (SAS) AF: 0.00171 AC: 8 AN: 4678

European-Finnish (FIN) AF: 0.000300 AC: 3 AN: 10012

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00167 AC: 112 AN: 66964

Other (OTH) AF: 0.00389 AC: 8 AN: 2058

Alfa AF: 0.0147 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs750206884; hg19: chr6-13286468; COSMIC: COSV60659577; COSMIC: COSV60659577;