14-35085787-GAA-GAAAA

Variant names:

• chr14-35085787-G-GAA
• rs201794373
• NM_017917.4:c.1174-11_1174-10dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017917.4(PPP2R3C):​c.1174-11_1174-10dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,012 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: 7.2e-7 (0 hom.)
• Consequence: PPP2R3C NM_017917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0310
• Publications: 0 publications found

Genes affected

PPP2R3C (HGNC:17485): (protein phosphatase 2 regulatory subunit B''gamma) This gene encodes a regulatory subunit of the serine/threonine phosphatase, protein phosphatase 2. This protein is localized to both nuclear and cytoplasmic regions depending on cell cycle phase. Homozygous conditional knockout mice for this gene exhibit reduced numbers and impaired proliferation of immune system B cells. This protein may regulate the expression of the P-glycoprotein ATP-binding cassette transporter through its phosphatase activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

FAM177A1 (HGNC:19829): (family with sequence similarity 177 member A1) This gene encodes a member of a conserved protein family. Alternative splicing results in multiple transcript variants. This gene is thought to be associated with susceptibility to juvenile idiopathic arthritis. [provided by RefSeq, Apr 2017]

FAM177A1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, G2P

LOC101927178 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017917.4. 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
	PPP2R3C	NM_017917.4	MANE Select	c.1174-11_1174-10dupTT		intron	N/A	NP_060387.2
	PPP2R3C	NM_001305155.2		c.844-11_844-10dupTT		intron	N/A	NP_001292084.1	Q969Q6-2
	PPP2R3C	NM_001305156.2		c.844-11_844-10dupTT		intron	N/A	NP_001292085.1	Q969Q6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R3C	ENST00000261475.10	TSL:1 MANE Select	c.1174-10_1174-9insTT		intron	N/A	ENSP00000261475.5	Q969Q6-1
	PPP2R3C	ENST00000553273.5	TSL:1	n.*840-10_*840-9insTT		intron	N/A	ENSP00000451075.1	G3V228
	PPP2R3C	ENST00000557217.5	TSL:1	n.*977-10_*977-9insTT		intron	N/A	ENSP00000452436.1	G3V228

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397012 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 695428

⚠️ 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: 30600

American (AMR) AF: 0.00 AC: 0 AN: 36540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24366

East Asian (EAS) AF: 0.00 AC: 0 AN: 38674

South Asian (SAS) AF: 0.00 AC: 0 AN: 79408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1073944

Other (OTH) AF: 0.00 AC: 0 AN: 57608

⚠️ 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		0.031
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: rs201794373; hg19: chr14-35554993;