chr14-94234639-G-A

Variant names:

• chr14-94234639-G-A
• rs749490429
• NM_058237.2:c.701G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_058237.2(PPP4R4):​c.701G>A​(p.Arg234Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000418 in 1,603,206 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: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: PPP4R4 NM_058237.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14754343).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058237.2. 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
	PPP4R4	NM_058237.2	MANE Select	c.701G>A	p.Arg234Gln	missense	Exon 7 of 25	NP_478144.1	Q6NUP7-1
	PPP4R4	NM_001348142.2		c.458G>A	p.Arg153Gln	missense	Exon 7 of 25	NP_001335071.1
	PPP4R4	NM_001348143.2		c.380G>A	p.Arg127Gln	missense	Exon 9 of 27	NP_001335072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP4R4	ENST00000304338.8	TSL:1 MANE Select	c.701G>A	p.Arg234Gln	missense	Exon 7 of 25	ENSP00000305924.3	Q6NUP7-1
	PPP4R4	ENST00000903467.1		c.701G>A	p.Arg234Gln	missense	Exon 7 of 25	ENSP00000573526.1
	PPP4R4	ENST00000941299.1		c.701G>A	p.Arg234Gln	missense	Exon 7 of 24	ENSP00000611358.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151916 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: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000798 AC: 20 AN: 250744 AF XY: 0.0000959

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000763

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000420 AC: 61 AN: 1451172 Hom.: 0 Cov.: 30 AF XY: 0.0000526 AC XY: 38 AN XY: 722542

African (AFR) AF: 0.0000903 AC: 3 AN: 33216

American (AMR) AF: 0.0000224 AC: 1 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.000784 AC: 31 AN: 39532

South Asian (SAS) AF: 0.000163 AC: 14 AN: 85880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000725 AC: 8 AN: 1102708

Other (OTH) AF: 0.0000666 AC: 4 AN: 60040

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

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	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.099
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.00060	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.28
Sift	Benign	0.23	T
Sift4G	Benign	0.12	T
Polyphen		0.059	B
Vest4		0.57
MutPred		0.58		Gain of catalytic residue at M232 (P = 0.0366)
MVP		0.64
MPC		0.45
ClinPred		0.098	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.29
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749490429; hg19: chr14-94700976;