rs1349571250

Variant names:

• chr19-3633462-G-A
• rs1349571250
• NM_012398.3:c.1979C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-3633462-G-A
• chr19-3633462-G-C
• chr19-3633462-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_012398.3(PIP5K1C):​c.1979C>T​(p.Pro660Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000122 in 1,471,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PIP5K1C NM_012398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

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

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2832645).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012398.3. 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.1979C>T	p.Pro660Leu	missense	Exon 17 of 18	NP_036530.1	O60331-1
	PIP5K1C	NM_001195733.2		c.1921-293C>T		intron	N/A	NP_001182662.1	O60331-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1979C>T	p.Pro660Leu	missense	Exon 17 of 18	ENSP00000335333.3	O60331-1
	PIP5K1C	ENST00000876625.1		c.2096C>T	p.Pro699Leu	missense	Exon 18 of 19	ENSP00000546684.1
	PIP5K1C	ENST00000967141.1		c.2081C>T	p.Pro694Leu	missense	Exon 17 of 18	ENSP00000637200.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151986 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 17 AN: 1319992 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 9 AN XY: 645326

African (AFR) AF: 0.0000341 AC: 1 AN: 29298

American (AMR) AF: 0.00 AC: 0 AN: 29174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19362

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36738

South Asian (SAS) AF: 0.0000473 AC: 3 AN: 63420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.0000106 AC: 11 AN: 1036860

Other (OTH) AF: 0.0000185 AC: 1 AN: 54160

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151986 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		6.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.083
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.031	B
Vest4		0.37
MutPred		0.18		Loss of catalytic residue at P659 (P = 0.0179)
MVP		0.13
MPC		0.35
ClinPred		0.88	D
GERP RS		3.4
Varity_R		0.095
Mutation Taster		=74/26	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: rs1349571250; hg19: chr19-3633460;