rs28493751

Variant names:

• chr17-6538056-G-A
• rs28493751
• NM_031220.4:c.49C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031220.4(PITPNM3):​c.49C>T​(p.Pro17Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0919 in 1,612,570 control chromosomes in the GnomAD database, including 7,452 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P17L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.082 (598 hom., cov: 32)
  • Exomes 𝑓: 0.093 (6854 hom.)
• Consequence: PITPNM3 NM_031220.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.82
• Publications: 21 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017623901).
• BP6: Variant 17-6538056-G-A is Benign according to our data. Variant chr17-6538056-G-A is described in ClinVar as [Benign]. Clinvar id is 261949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITPNM3	NM_031220.4	c.49C>T	p.Pro17Ser	missense_variant	Exon 2 of 20	ENST00000262483.13	NP_112497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM3	ENST00000262483.13	c.49C>T	p.Pro17Ser	missense_variant	Exon 2 of 20	1	NM_031220.4	ENSP00000262483.8
PITPNM3	ENST00000421306.7	c.49C>T	p.Pro17Ser	missense_variant	Exon 2 of 19	2		ENSP00000407882.3

Frequencies

GnomAD3 genomes AF: 0.0820 AC: 12461 AN: 152054 Hom.: 598 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0823

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.00678

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0847

GnomAD2 exomes AF: 0.0836 AC: 20927 AN: 250446 AF XY: 0.0859

Gnomad AFR exome AF: 0.0391

Gnomad AMR exome AF: 0.0599

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.0109

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0970

GnomAD4 exome AF: 0.0929 AC: 135653 AN: 1460398 Hom.: 6854 Cov.: 32 AF XY: 0.0926 AC XY: 67296 AN XY: 726588

African (AFR) AF: 0.0426 AC: 1425 AN: 33442

American (AMR) AF: 0.0610 AC: 2727 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4516 AN: 26122

East Asian (EAS) AF: 0.00499 AC: 198 AN: 39696

South Asian (SAS) AF: 0.0639 AC: 5509 AN: 86208

European-Finnish (FIN) AF: 0.103 AC: 5497 AN: 53370

Middle Eastern (MID) AF: 0.128 AC: 740 AN: 5766

European-Non Finnish (NFE) AF: 0.0982 AC: 109083 AN: 1110748

Other (OTH) AF: 0.0988 AC: 5958 AN: 60330

GnomAD4 genome AF: 0.0819 AC: 12470 AN: 152172 Hom.: 598 Cov.: 32 AF XY: 0.0823 AC XY: 6125 AN XY: 74380

African (AFR) AF: 0.0435 AC: 1807 AN: 41540

American (AMR) AF: 0.0822 AC: 1256 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 666 AN: 3472

East Asian (EAS) AF: 0.00680 AC: 35 AN: 5150

South Asian (SAS) AF: 0.0638 AC: 308 AN: 4824

European-Finnish (FIN) AF: 0.107 AC: 1129 AN: 10600

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6963 AN: 67980

Other (OTH) AF: 0.0838 AC: 177 AN: 2112

Alfa AF: 0.0935 Hom.: 2661

Bravo AF: 0.0776

TwinsUK AF: 0.102 AC: 379

ALSPAC AF: 0.0926 AC: 357

ESP6500AA AF: 0.0445 AC: 196

ESP6500EA AF: 0.109 AC: 939

ExAC AF: 0.0824 AC: 9998

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.114

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 16, 2018

GeneDx

Significance: 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 5 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	.;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		3.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.10
Sift	Benign	0.28	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.68	.;P
Vest4		0.33
MPC		1.0
ClinPred		0.020	T
GERP RS		4.9
Varity_R		0.097
gMVP		0.073
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28493751; hg19: chr17-6441376; COSMIC: COSV52592722;