rs150414663

Variant names:

• chr19-3637458-C-T
• rs150414663
• ENST00000589578.5:c.2076G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001300849.2(PIP5K1C):​c.2076G>A​(p.Pro692Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,535,700 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (31 hom.)
• Consequence: PIP5K1C NM_001300849.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.23
• Publications: 2 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-3637458-C-T is Benign according to our data. Variant chr19-3637458-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2649003.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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+1426G>A		intron	N/A	NP_036530.1	O60331-1
	PIP5K1C	NM_001300849.2		c.2076G>A	p.Pro692Pro	synonymous	Exon 17 of 17	NP_001287778.1	O60331-3
	PIP5K1C	NM_001195733.2		c.1920+1426G>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.2076G>A	p.Pro692Pro	synonymous	Exon 17 of 17	ENSP00000466363.1	O60331-3
	PIP5K1C	ENST00000537021.1	TSL:1	c.*366G>A		3_prime_UTR	Exon 17 of 17	ENSP00000444779.1	O60331-2
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1920+1426G>A		intron	N/A	ENSP00000335333.3	O60331-1

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152186 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00409 AC: 542 AN: 132648 AF XY: 0.00404

Gnomad AFR exome AF: 0.000631

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.00985

Gnomad EAS exome AF: 0.0000954

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00548

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00472 AC: 6532 AN: 1383396 Hom.: 31 Cov.: 57 AF XY: 0.00482 AC XY: 3289 AN XY: 682618

African (AFR) AF: 0.00127 AC: 40 AN: 31590

American (AMR) AF: 0.00146 AC: 52 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 254 AN: 25172

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35726

South Asian (SAS) AF: 0.00454 AC: 360 AN: 79236

European-Finnish (FIN) AF: 0.000892 AC: 30 AN: 33616

Middle Eastern (MID) AF: 0.0121 AC: 69 AN: 5696

European-Non Finnish (NFE) AF: 0.00504 AC: 5437 AN: 1078782

Other (OTH) AF: 0.00499 AC: 289 AN: 57886

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152304 Hom.: 3 Cov.: 31 AF XY: 0.00283 AC XY: 211 AN XY: 74466

African (AFR) AF: 0.000625 AC: 26 AN: 41574

American (AMR) AF: 0.00261 AC: 40 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00513 AC: 349 AN: 68018

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00515 Hom.: 1

Bravo AF: 0.00324

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.053
DANN	Benign	0.56
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	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: rs150414663; hg19: chr19-3637456;