14-35085787-GAA-GA

Variant names:

• chr14-35085787-GA-G
• rs201794373
• NM_017917.4:c.1174-10delT

Variant summary

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

The NM_017917.4(PPP2R3C):​c.1174-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000873 in 1,546,270 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 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (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 0 ACMG points.

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.1174-10delT		intron	N/A	NP_060387.2
	PPP2R3C	NM_001305155.2		c.844-10delT		intron	N/A	NP_001292084.1	Q969Q6-2
	PPP2R3C	NM_001305156.2		c.844-10delT		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.1174-10delT		intron	N/A	ENSP00000261475.5	Q969Q6-1
	PPP2R3C	ENST00000553273.5	TSL:1	n.*840-10delT		intron	N/A	ENSP00000451075.1	G3V228
	PPP2R3C	ENST00000557217.5	TSL:1	n.*977-10delT		intron	N/A	ENSP00000452436.1	G3V228

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150356 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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000335 AC: 60 AN: 179080 AF XY: 0.000370

Gnomad AFR exome AF: 0.000234

Gnomad AMR exome AF: 0.000420

Gnomad ASJ exome AF: 0.000761

Gnomad EAS exome AF: 0.000524

Gnomad FIN exome AF: 0.000321

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.000238

GnomAD4 exome AF: 0.0000960 AC: 134 AN: 1395914 Hom.: 0 Cov.: 29 AF XY: 0.0000979 AC XY: 68 AN XY: 694892

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

African (AFR) AF: 0.000196 AC: 6 AN: 30576

American (AMR) AF: 0.000192 AC: 7 AN: 36458

Ashkenazi Jewish (ASJ) AF: 0.000123 AC: 3 AN: 24342

East Asian (EAS) AF: 0.0000776 AC: 3 AN: 38646

South Asian (SAS) AF: 0.000114 AC: 9 AN: 79264

European-Finnish (FIN) AF: 0.000179 AC: 9 AN: 50310

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5494

European-Non Finnish (NFE) AF: 0.0000839 AC: 90 AN: 1073272

Other (OTH) AF: 0.000104 AC: 6 AN: 57552

⚠️ 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: 0.00000665 AC: 1 AN: 150356 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73274

African (AFR) AF: 0.00 AC: 0 AN: 40942

American (AMR) AF: 0.00 AC: 0 AN: 15086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67526

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00226 Hom.: 0

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

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: rs201794373; hg19: chr14-35554993; COSMIC: COSV54835499; COSMIC: COSV54835499;