rs11654175

Positions:

• chr17-6470417-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031220.4(PITPNM3):​c.1625-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,613,536 control chromosomes in the GnomAD database, including 148,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11240 hom., cov: 33)
  • Exomes 𝑓: 0.43 (137527 hom.)
• Consequence: PITPNM3 NM_031220.4 intron
• Scores: Splicing: ADA: 0.00009036
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.428

Genes affected

PITPNM3 (HGNC:21043): (PITPNM family member 3) This gene encodes a member of a family of membrane-associated phosphatidylinositol transfer domain-containing proteins. The calcium-binding protein has phosphatidylinositol (PI) transfer activity and interacts with the protein tyrosine kinase PTK2B (also known as PYK2). The protein is homologous to a Drosophila protein that is implicated in the visual transduction pathway in flies. Mutations in this gene result in autosomal dominant cone dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

PITPNM3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-6470417-C-T is Benign according to our data. Variant chr17-6470417-C-T is described in ClinVar as [Benign]. Clinvar id is 194273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITPNM3	NM_031220.4	c.1625-9G>A		intron_variant		ENST00000262483.13	NP_112497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITPNM3	ENST00000262483.13	c.1625-9G>A		intron_variant		1	NM_031220.4	ENSP00000262483.8
PITPNM3	ENST00000572795.1	n.4131-9G>A		intron_variant		1
PITPNM3	ENST00000576664.5	n.374-9G>A		intron_variant		1
PITPNM3	ENST00000421306.7	c.1517-9G>A		intron_variant		2		ENSP00000407882.3

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55545 AN: 151942 Hom.: 11240 Cov.: 33

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.377 AC: 94198 AN: 249992 Hom.: 19252 AF XY: 0.380 AC XY: 51393 AN XY: 135412

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.247

Gnomad FIN exome AF: 0.424

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.426 AC: 623070 AN: 1461476 Hom.: 137527 Cov.: 60 AF XY: 0.423 AC XY: 307435 AN XY: 727016

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.467

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.417

GnomAD4 genome AF: 0.365 AC: 55548 AN: 152060 Hom.: 11240 Cov.: 33 AF XY: 0.362 AC XY: 26940 AN XY: 74320

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.459

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.464

Gnomad4 OTH AF: 0.412

Alfa AF: 0.424 Hom.: 5927

Bravo AF: 0.358

Asia WGS AF: 0.220 AC: 771 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2016	- -

Cone-rod dystrophy 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000090
dbscSNV1_RF	Benign	0.0020
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

LitVar

Other links and lift over

dbSNP: rs11654175; hg19: chr17-6373737; COSMIC: COSV52592826;