14-94174485-C-T

Variant names:

• chr14-94174485-C-T
• NM_058237.2:c.20C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_058237.2(PPP4R4):​c.20C>T​(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP4R4 NM_058237.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.100

Genes affected

PPP4R4 (HGNC:23788): (protein phosphatase 4 regulatory subunit 4) The protein encoded by this gene is a HEAT-like repeat-containing protein. The HEAT repeat is a tandemly repeated, 37-47 amino acid long module occurring in a number of cytoplasmic proteins. Arrays of HEAT repeats form a rod-like helical structure and appear to function as protein-protein interaction surfaces. The repeat-containing region of this protein has some similarity to the constant regulatory domain of the protein phosphatase 2A PR65/A subunit. The encoded protein binds protein serine/threonine phosphatase 4c in the cytoplasm. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105520815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP4R4	NM_058237.2	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 25	ENST00000304338.8	NP_478144.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP4R4	ENST00000304338.8	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 25	1	NM_058237.2	ENSP00000305924.3
PPP4R4	ENST00000328839.3	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 5	1		ENSP00000330831.3
PPP4R4	ENST00000556884.5	c.-126-1569C>T		intron_variant	Intron 2 of 5	4		ENSP00000452121.1
PPP4R4	ENST00000555690.5	n.174C>T		non_coding_transcript_exon_variant	Exon 1 of 5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20C>T (p.A7V) alteration is located in exon 1 (coding exon 1) of the PPP4R4 gene. This alteration results from a C to T substitution at nucleotide position 20, causing the alanine (A) at amino acid position 7 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.49	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.0070
Sift	Benign	0.18	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.048	B;B
Vest4		0.12
MutPred		0.30		Gain of catalytic residue at P3 (P = 0);Gain of catalytic residue at P3 (P = 0);
MVP		0.030
MPC		0.28
ClinPred		0.10	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.021
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-94640822;