rs552785133

Variant names:

• chr19-3637454-C-A
• rs552785133
• ENST00000589578.5:c.2080G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-3637454-C-A
• chr19-3637454-C-G
• chr19-3637454-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001300849.2(PIP5K1C):​c.2080G>T​(p.Ala694Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A694P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PIP5K1C NM_001300849.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.142
• Publications: 0 publications found

Genes affected

PIP5K1C (HGNC:8996): (phosphatidylinositol-4-phosphate 5-kinase type 1 gamma) This locus encodes a type I phosphatidylinositol 4-phosphate 5-kinase. The encoded protein catalyzes phosphorylation of phosphatidylinositol 4-phosphate, producing phosphatidylinositol 4,5-bisphosphate. This enzyme is found at synapses and has been found to play roles in endocytosis and cell migration. Mutations at this locus have been associated with lethal congenital contractural syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Sep 2010]

PIP5K1C Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07029948).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300849.2. 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
	PIP5K1C	NM_012398.3	MANE Select	c.1920+1430G>T		intron	N/A	NP_036530.1	O60331-1
	PIP5K1C	NM_001300849.2		c.2080G>T	p.Ala694Ser	missense	Exon 17 of 17	NP_001287778.1	O60331-3
	PIP5K1C	NM_001195733.2		c.1920+1430G>T		intron	N/A	NP_001182662.1	O60331-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP5K1C	ENST00000589578.5	TSL:1	c.2080G>T	p.Ala694Ser	missense	Exon 17 of 17	ENSP00000466363.1	O60331-3
	PIP5K1C	ENST00000537021.1	TSL:1	c.*370G>T		3_prime_UTR	Exon 17 of 17	ENSP00000444779.1	O60331-2
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1920+1430G>T		intron	N/A	ENSP00000335333.3	O60331-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383394 Hom.: 0 Cov.: 58 AF XY: 0.00 AC XY: 0 AN XY: 682614

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078786

Other (OTH) AF: 0.00 AC: 0 AN: 57886

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.32
DANN	Benign	0.44
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.070	T
PhyloP100		-0.14
Polyphen		0.0	B
Vest4		0.066
MVP		0.068
GERP RS		-2.4
gMVP		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs552785133; hg19: chr19-3637452; COSMIC: COSV58954905;