chr14-94174568-C-T

Variant names:

• chr14-94174568-C-T
• rs746032028
• NM_058237.2:c.103C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001348143.2(PPP4R4):​c.-590C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000137 in 1,459,520 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPP4R4 NM_001348143.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.68
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348143.2. 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.103C>T	p.Arg35Cys	missense	Exon 1 of 25	NP_478144.1	Q6NUP7-1
	PPP4R4	NM_001348143.2		c.-590C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	NP_001335072.1
	PPP4R4	NM_001348144.2		c.-323C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 26	NP_001335073.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP4R4	ENST00000304338.8	TSL:1 MANE Select	c.103C>T	p.Arg35Cys	missense	Exon 1 of 25	ENSP00000305924.3	Q6NUP7-1
	PPP4R4	ENST00000328839.3	TSL:1	c.103C>T	p.Arg35Cys	missense	Exon 1 of 5	ENSP00000330831.3	Q6NUP7-2
	PPP4R4	ENST00000903467.1		c.103C>T	p.Arg35Cys	missense	Exon 1 of 25	ENSP00000573526.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459520 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726180

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111100

Other (OTH) AF: 0.00 AC: 0 AN: 60212

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.91	P
Vest4		0.42
MutPred		0.44		Loss of disorder (P = 0.0104)
MVP		0.33
MPC		0.95
ClinPred		1.0	D
GERP RS		2.9
PromoterAI		0.0047	Neutral
Varity_R		0.42
gMVP		0.62
Mutation Taster		=71/29	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: rs746032028; hg19: chr14-94640905;