chr17-6468237-C-G

Position:

chr17-6468237-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_031220.4(PITPNM3):c.1878G>C(p.Gln626His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,613,304 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 30 hom. )

Consequence

PITPNM3
NM_031220.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:5

Conservation

PhyloP100: 0.740

Variant links:

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 links:

PITPNM3 (HGNC:):

PITPNM3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013042867).

BS2

High AC in GnomAd4 at 318 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITPNM3	NM_031220.4 linkuse as main transcript	c.1878G>C	p.Gln626His	missense_variant	14/20	ENST00000262483.13	NP_112497.2	Q9BZ71-1
PITPNM3	NM_001165966.2 linkuse as main transcript	c.1770G>C	p.Gln590His	missense_variant	13/19		NP_001159438.1	A1A5C9
PITPNM3	XM_011524015.4 linkuse as main transcript	c.1878G>C	p.Gln626His	missense_variant	14/19		XP_011522317.1
PITPNM3	XM_011524016.4 linkuse as main transcript	c.1878G>C	p.Gln626His	missense_variant	14/18		XP_011522318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PITPNM3	ENST00000262483.13 linkuse as main transcript	c.1878G>C	p.Gln626His	missense_variant	14/20	1	NM_031220.4	ENSP00000262483.8	Q9BZ71-1
PITPNM3	ENST00000572795.1 linkuse as main transcript	n.4384G>C		non_coding_transcript_exon_variant	8/14	1
PITPNM3	ENST00000576664.5 linkuse as main transcript	n.627G>C		non_coding_transcript_exon_variant	5/11	1
PITPNM3	ENST00000421306.7 linkuse as main transcript	c.1770G>C	p.Gln590His	missense_variant	13/19	2		ENSP00000407882.3	Q9BZ71-3

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00369

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00160

AC:

401

AN:

250184

Hom.:

AF XY:

0.00158

AC XY:

214

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.00313

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00392

AC:

5727

AN:

1460954

Hom.:

Cov.:

AF XY:

0.00373

AC XY:

2709

AN XY:

726740

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00490

Gnomad4 OTH exome

AF:

0.00353

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152350

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00369

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00212

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00144

AC:

175

EpiCase

AF:

0.00360

EpiControl

AF:

0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cone-rod dystrophy 5

Pathogenic:1Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	- -
Pathogenic, flagged submission	literature only	OMIM	Jun 01, 2007	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A heterozygous missense variant was identified, NM_031220.3(PITPNM3):c.1878G>C in exon 14 of the PITPNM3 gene. This substitution is predicted to create a minor amino acid change from a glutamine to a histidine at position 626 of the protein; NP_112497.2(PITPNM3):p.(Gln626His). The glutamine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predicts this variant to be tolerated (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.16% (455 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.31%. This variant has been previously reported with conflicting interpretations of pathogenicity in patients with cone-rod dystrophy (ClinVar, Reinis A. et al. (2013), Zhao, L. et al (2015), Khan, K. et al (2017), Jespersgaard, C. et al. (2019)). Based on information available at the time of curation, this variant has been classified as LIKELY BENIGN. -

not provided

Pathogenic:1Uncertain:1Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2017

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. -

PITPNM3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.42

DEOGEN2

Benign

0.021

.;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

.;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

1.9

N;N

REVEL

Benign

0.26

Sift

Benign

0.66

T;T

Sift4G

Benign

0.80

T;T

Polyphen

0.0010

.;B

Vest4

0.59

MutPred

0.75

.;Gain of sheet (P = 0.1451);

MVP

0.73

MPC

0.44

ClinPred

0.0045

GERP RS

3.9

Varity_R

0.052

gMVP

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over