chr6-13286236-GT-G

Variant names:

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

Variant summary

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

The NM_001374581.2(PHACTR1):​c.1751delT​(p.Phe584SerfsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,433,668 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (0 hom.)
• Consequence: PHACTR1 NM_001374581.2 frameshift
• Clinical Significance: Not reported in ClinVar
• 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 -2 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 0.0223 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd4 at 14 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+24delT		intron	N/A	NP_112210.1	Q9C0D0-1
	PHACTR1	NM_001374581.2		c.1751delT	p.Phe584SerfsTer71	frameshift	Exon 13 of 13	NP_001361510.1	A0A6Q8PG87
	PHACTR1	NM_001374583.2		c.1475delT	p.Phe492SerfsTer71	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+24delT		intron	N/A	ENSP00000329880.8	Q9C0D0-1
	PHACTR1	ENST00000674595.1		c.1751delT	p.Phe584SerfsTer71	frameshift	Exon 13 of 13	ENSP00000502157.1	A0A6Q8PG87
	PHACTR1	ENST00000675203.2		c.1937+24delT		intron	N/A	ENSP00000502172.2	A0A6Q8PGC2

Frequencies

GnomAD3 genomes AF: 0.0000941 AC: 14 AN: 148832 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000590

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000448

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00958 AC: 1061 AN: 110754 AF XY: 0.00957

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.00745

Gnomad ASJ exome AF: 0.00360

Gnomad EAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00554

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00941

GnomAD4 exome AF: 0.000778 AC: 999 AN: 1284836 Hom.: 0 Cov.: 29 AF XY: 0.000865 AC XY: 549 AN XY: 634396

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

African (AFR) AF: 0.00150 AC: 42 AN: 28018

American (AMR) AF: 0.00290 AC: 78 AN: 26858

Ashkenazi Jewish (ASJ) AF: 0.000832 AC: 18 AN: 21632

East Asian (EAS) AF: 0.00281 AC: 97 AN: 34572

South Asian (SAS) AF: 0.00115 AC: 77 AN: 67038

European-Finnish (FIN) AF: 0.00153 AC: 71 AN: 46508

Middle Eastern (MID) AF: 0.000195 AC: 1 AN: 5138

European-Non Finnish (NFE) AF: 0.000566 AC: 567 AN: 1002362

Other (OTH) AF: 0.000911 AC: 48 AN: 52710

⚠️ 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: 0.0000941 AC: 14 AN: 148832 Hom.: 0 Cov.: 32 AF XY: 0.0000965 AC XY: 7 AN XY: 72508

African (AFR) AF: 0.000198 AC: 8 AN: 40500

American (AMR) AF: 0.00 AC: 0 AN: 14864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000590 AC: 3 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000448 AC: 3 AN: 66986

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.000106

ClinVar

Not reported in ClinVar

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: COSV60663512; COSMIC: COSV60663512;