chr14-35085673-A-T

Variant names:

• chr14-35085673-A-T
• rs1384540937
• NM_017917.4:c.1279T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017917.4(PPP2R3C):​c.1279T>A​(p.Leu427Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PPP2R3C NM_017917.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3420732).

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.1279T>A	p.Leu427Met	missense	Exon 13 of 13	NP_060387.2
	PPP2R3C	NM_001305155.2		c.949T>A	p.Leu317Met	missense	Exon 12 of 12	NP_001292084.1	Q969Q6-2
	PPP2R3C	NM_001305156.2		c.949T>A	p.Leu317Met	missense	Exon 13 of 13	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.1279T>A	p.Leu427Met	missense	Exon 13 of 13	ENSP00000261475.5	Q969Q6-1
	PPP2R3C	ENST00000553273.5	TSL:1	n.*945T>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000451075.1	G3V228
	PPP2R3C	ENST00000557217.5	TSL:1	n.*1082T>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000452436.1	G3V228

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461226 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726952

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111492

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.097
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.35
Sift	Benign	0.043	D
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.63
MutPred		0.40		Gain of sheet (P = 0.0827)
MVP		0.22
MPC		1.2
ClinPred		0.75	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.39
Mutation Taster		=65/35	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: rs1384540937; hg19: chr14-35554879;