rs76024428

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 15/22 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:1U:4B:6

Conservation

PhyloP100: 0.740

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

cone-rod dystrophy 5
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PITPNM3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

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

BP6

Variant 17-6468237-C-G is Benign according to our data. Variant chr17-6468237-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1994.

BS2

High AC in GnomAd4 at 318 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITPNM3	NM_031220.4 link	c.1878G>C	p.Gln626His	missense_variant	Exon 14 of 20	ENST00000262483.13	NP_112497.2	Q9BZ71-1
PITPNM3	NM_001165966.2 link	c.1770G>C	p.Gln590His	missense_variant	Exon 13 of 19		NP_001159438.1	A1A5C9
PITPNM3	XM_011524015.4 link	c.1878G>C	p.Gln626His	missense_variant	Exon 14 of 19		XP_011522317.1
PITPNM3	XM_011524016.4 link	c.1878G>C	p.Gln626His	missense_variant	Exon 14 of 18		XP_011522318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PITPNM3	ENST00000262483.13 link	c.1878G>C	p.Gln626His	missense_variant	Exon 14 of 20	1	NM_031220.4	ENSP00000262483.8	Q9BZ71-1
PITPNM3	ENST00000572795.1 link	n.4384G>C		non_coding_transcript_exon_variant	Exon 8 of 14	1
PITPNM3	ENST00000576664.5 link	n.627G>C		non_coding_transcript_exon_variant	Exon 5 of 11	1
PITPNM3	ENST00000421306.7 link	c.1770G>C	p.Gln590His	missense_variant	Exon 13 of 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

GnomAD2 exomes

AF:

0.00160

AC:

401

AN:

250184

AF XY:

0.00158

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 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

African (AFR)

AF:

0.000598

AC:

AN:

33454

American (AMR)

AF:

0.000738

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5092

European-Non Finnish (NFE)

AF:

0.00490

AC:

5447

AN:

1111960

Other (OTH)

AF:

0.00353

AC:

213

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

294

587

881

1174

1468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152350

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41584

American (AMR)

AF:

0.00105

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00369

AC:

251

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:1Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cone-rod dystrophy 5

Pathogenic:1Uncertain:1Benign:2

Jun 01, 2007

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 01, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PITPNM3: BS1 -

Feb 20, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Uncertain:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Benign:1

Oct 19, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 14, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.74

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

Mutation Taster

=70/30

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over