6-13286236-GTT-GTTTT

Variant names:

• chr6-13286236-G-GTT
• rs750206884
• NM_030948.6:c.1727+23_1727+24dupTT

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.1750_1751dupTT​(p.Leu585SerfsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000918 in 1,437,546 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 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (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 0.0218 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd4 at 6 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+23_1727+24dupTT		intron	N/A	NP_112210.1	Q9C0D0-1
	PHACTR1	NM_001374581.2		c.1750_1751dupTT	p.Leu585SerfsTer71	frameshift	Exon 13 of 13	NP_001361510.1	A0A6Q8PG87
	PHACTR1	NM_001374583.2		c.1474_1475dupTT	p.Leu493SerfsTer71	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+23_1727+24dupTT		intron	N/A	ENSP00000329880.8	Q9C0D0-1
	PHACTR1	ENST00000674595.1		c.1750_1751dupTT	p.Leu585SerfsTer71	frameshift	Exon 13 of 13	ENSP00000502157.1	A0A6Q8PG87
	PHACTR1	ENST00000675203.2		c.1937+23_1937+24dupTT		intron	N/A	ENSP00000502172.2	A0A6Q8PGC2

Frequencies

GnomAD3 genomes AF: 0.0000403 AC: 6 AN: 148836 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000896

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000153 AC: 17 AN: 110754 AF XY: 0.000187

Gnomad AFR exome AF: 0.000415

Gnomad AMR exome AF: 0.0000856

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000265

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000175

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000978 AC: 126 AN: 1288598 Hom.: 0 Cov.: 29 AF XY: 0.000118 AC XY: 75 AN XY: 636474

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

African (AFR) AF: 0.000107 AC: 3 AN: 28104

American (AMR) AF: 0.0000370 AC: 1 AN: 26994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21738

East Asian (EAS) AF: 0.0000576 AC: 2 AN: 34750

South Asian (SAS) AF: 0.0000445 AC: 3 AN: 67378

European-Finnish (FIN) AF: 0.0000214 AC: 1 AN: 46756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 0.000113 AC: 114 AN: 1004858

Other (OTH) AF: 0.0000378 AC: 2 AN: 52868

⚠️ 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: 0.0000403 AC: 6 AN: 148948 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 2 AN XY: 72634

African (AFR) AF: 0.00 AC: 0 AN: 40622

American (AMR) AF: 0.00 AC: 0 AN: 14884

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000896 AC: 6 AN: 66982

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.0000416

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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750206884; hg19: chr6-13286468;