rs750206884

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-13286236-GTT-G
• chr6-13286236-GTT-GT
• chr6-13286236-GTT-GTTT
• chr6-13286236-GTT-GTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001374581.2(PHACTR1):​c.1750_1751delTT​(p.Phe584ProfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000776 in 1,289,352 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: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: PHACTR1 NM_001374581.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• 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: Uncertain_significance. 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 0.0229 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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+24delTT		intron	N/A	NP_112210.1	Q9C0D0-1
	PHACTR1	NM_001374581.2		c.1750_1751delTT	p.Phe584ProfsTer45	frameshift	Exon 13 of 13	NP_001361510.1	A0A6Q8PG87
	PHACTR1	NM_001374583.2		c.1474_1475delTT	p.Phe492ProfsTer45	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+24delTT		intron	N/A	ENSP00000329880.8	Q9C0D0-1
	PHACTR1	ENST00000674595.1		c.1750_1751delTT	p.Phe584ProfsTer45	frameshift	Exon 13 of 13	ENSP00000502157.1	A0A6Q8PG87
	PHACTR1	ENST00000675203.2		c.1937+23_1937+24delTT		intron	N/A	ENSP00000502172.2	A0A6Q8PGC2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.76e-7 AC: 1 AN: 1289352 Hom.: 0 AF XY: 0.00000157 AC XY: 1 AN XY: 636882

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

African (AFR) AF: 0.00 AC: 0 AN: 28124

American (AMR) AF: 0.00 AC: 0 AN: 27040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21746

East Asian (EAS) AF: 0.00 AC: 0 AN: 34770

South Asian (SAS) AF: 0.00 AC: 0 AN: 67452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5154

European-Non Finnish (NFE) AF: 9.95e-7 AC: 1 AN: 1005392

Other (OTH) AF: 0.00 AC: 0 AN: 52900

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
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;