17-67675537-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_012417.4(PITPNC1):c.677G>T(p.Trp226Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W226G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PITPNC1 NM_012417.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.84

Genes affected

PITPNC1 (HGNC:21045): (phosphatidylinositol transfer protein cytoplasmic 1) This gene encodes a member of the phosphatidylinositol transfer protein family. The encoded cytoplasmic protein plays a role in multiple processes including cell signaling and lipid metabolism by facilitating the transfer of phosphatidylinositol between membrane compartments. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 1. [provided by RefSeq, May 2012]

LOC101928045 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITPNC1	NM_012417.4	c.677G>T	p.Trp226Leu	missense_variant	8/9	ENST00000581322.6
LOC101928045	XR_002958126.2	n.418C>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITPNC1	ENST00000581322.6	c.677G>T	p.Trp226Leu	missense_variant	8/9	1	NM_012417.4
PITPNC1	ENST00000580974.6	c.677G>T	p.Trp226Leu	missense_variant	8/10	1		P1
PITPNC1	ENST00000578527.1	n.815G>T		non_coding_transcript_exon_variant	5/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.677G>T (p.W226L) alteration is located in exon 8 (coding exon 8) of the PITPNC1 gene. This alteration results from a G to T substitution at nucleotide position 677, causing the tryptophan (W) at amino acid position 226 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	33
Dann	Benign	0.95
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.91
MutPred		0.76		.;Loss of catalytic residue at M229 (P = 0.0045);Loss of catalytic residue at M229 (P = 0.0045);
MVP		0.81
MPC		2.2
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.98

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-65671653;