17-1534170-C-G

Position:

• chr17-1534170-C-G

Variant summary

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

The NM_006224.4(PITPNA):​c.697G>C​(p.Asp233His) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PITPNA NM_006224.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

PITPNA (HGNC:9001): (phosphatidylinositol transfer protein alpha) This gene encodes a member of a family of lipid-binding proteins that transfer molecules of phosphatidylinositol or phosphatidylcholine between membrane surfaces. The protein is implicated in phospholipase C signaling and in the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by phosphoinositide-3-kinase.[provided by RefSeq, Sep 2009]

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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITPNA	NM_006224.4	c.697G>C	p.Asp233His	missense_variant	10/12	ENST00000313486.12	NP_006215.1
PITPNA	XM_047436299.1	c.478G>C	p.Asp160His	missense_variant	10/12		XP_047292255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITPNA	ENST00000313486.12	c.697G>C	p.Asp233His	missense_variant	10/12	5	NM_006224.4	ENSP00000316809.7
PITPNA	ENST00000574991.5	c.625G>C	p.???209???	splice_region_variant, synonymous_variant	9/9	3		ENSP00000461245.1
PITPNA	ENST00000575288.5	n.*317G>C		non_coding_transcript_exon_variant	8/10	2		ENSP00000461011.1
PITPNA	ENST00000575288.5	n.*317G>C		3_prime_UTR_variant	8/10	2		ENSP00000461011.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Sep 02, 2024

The c.697G>C (p.D233H) alteration is located in exon 10 (coding exon 10) of the PITPNA gene. This alteration results from a G to C substitution at nucleotide position 697, causing the aspartic acid (D) at amino acid position 233 to be replaced by a histidine (H). 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	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.94		Gain of MoRF binding (P = 0.0452);Gain of MoRF binding (P = 0.0452);
MVP		0.85
MPC		2.1
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.91
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: chr17-1437464;