ENST00000589578.5:c.1980G>A

Variant names:

• chr19-3637554-C-T
• rs561346539
• ENST00000589578.5:c.1980G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The ENST00000589578.5(PIP5K1C):​c.1980G>A​(p.Thr660Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,530,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T660T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: PIP5K1C ENST00000589578.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.367
• Publications: 1 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP7: Synonymous conserved (PhyloP=0.367 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589578.5. 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+1330G>A		intron	N/A	NP_036530.1	O60331-1
	PIP5K1C	NM_001300849.2		c.1980G>A	p.Thr660Thr	synonymous	Exon 17 of 17	NP_001287778.1	O60331-3
	PIP5K1C	NM_001195733.2		c.1920+1330G>A		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.1980G>A	p.Thr660Thr	synonymous	Exon 17 of 17	ENSP00000466363.1	O60331-3
	PIP5K1C	ENST00000537021.1	TSL:1	c.*270G>A		3_prime_UTR	Exon 17 of 17	ENSP00000444779.1	O60331-2
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1920+1330G>A		intron	N/A	ENSP00000335333.3	O60331-1

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150252 Hom.: 0 Cov.: 31

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000746 AC: 1 AN: 134106 AF XY: 0.0000137

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000435 AC: 6 AN: 1380588 Hom.: 0 Cov.: 57 AF XY: 0.00000294 AC XY: 2 AN XY: 681070

African (AFR) AF: 0.00 AC: 0 AN: 31530

American (AMR) AF: 0.00 AC: 0 AN: 35608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25090

East Asian (EAS) AF: 0.00 AC: 0 AN: 35556

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076748

Other (OTH) AF: 0.0000173 AC: 1 AN: 57686

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150252 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73286

African (AFR) AF: 0.00 AC: 0 AN: 41030

American (AMR) AF: 0.00 AC: 0 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5016

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67484

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs561346539; hg19: chr19-3637552;