14-35091134-A-G

Position:

• chr14-35091134-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_017917.4(PPP2R3C):​c.1049T>C​(p.Phe350Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PPP2R3C NM_017917.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.04

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]

PPP2R3C (HGNC:):

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 14-35091134-A-G is Pathogenic according to our data. Variant chr14-35091134-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 627423.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R3C	NM_017917.4	c.1049T>C	p.Phe350Ser	missense_variant	11/13	ENST00000261475.10	NP_060387.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R3C	ENST00000261475.10	c.1049T>C	p.Phe350Ser	missense_variant	11/13	1	NM_017917.4	ENSP00000261475.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	School of Medicine, Marmara University	-	Syndromic 46, XY Gonadal Dysgenesis and Impaired Spermatogenesis in humans -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 31, 2022	- -

Spermatogenic failure 36 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.73		Loss of stability (P = 0.0268);
MVP		0.92
MPC		1.6
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs1566684983; hg19: chr14-35560340; COSMIC: COSV99808764; COSMIC: COSV99808764;