rs73346359

Variant names:

• chr17-6461561-T-C
• rs73346359
• NM_031220.4:c.2307-5A>G

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.2307-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0577 in 1,613,868 control chromosomes in the GnomAD database, including 3,574 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (730 hom., cov: 33)
  • Exomes 𝑓: 0.055 (2844 hom.)
• Consequence: PITPNM3 NM_031220.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003512
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.21
• Publications: 6 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 (BayesDel_noAF=-0.94).
• BP6: Variant 17-6461561-T-C is Benign according to our data. Variant chr17-6461561-T-C is described in ClinVar as Benign. ClinVar VariationId is 261944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITPNM3	NM_031220.4	c.2307-5A>G		splice_region_variant, intron_variant	Intron 17 of 19	ENST00000262483.13	NP_112497.2
PITPNM3	NM_001165966.2	c.2199-5A>G		splice_region_variant, intron_variant	Intron 16 of 18		NP_001159438.1
PITPNM3	XM_011524015.4	c.2307-5A>G		splice_region_variant, intron_variant	Intron 17 of 18		XP_011522317.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM3	ENST00000262483.13	c.2307-5A>G		splice_region_variant, intron_variant	Intron 17 of 19	1	NM_031220.4	ENSP00000262483.8

Frequencies

GnomAD3 genomes AF: 0.0832 AC: 12653 AN: 152140 Hom.: 719 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0386

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.0663

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0611

GnomAD2 exomes AF: 0.0594 AC: 14933 AN: 251260 AF XY: 0.0575

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.0657

Gnomad NFE exome AF: 0.0467

Gnomad OTH exome AF: 0.0458

GnomAD4 exome AF: 0.0551 AC: 80495 AN: 1461610 Hom.: 2844 Cov.: 36 AF XY: 0.0543 AC XY: 39487 AN XY: 727116

African (AFR) AF: 0.164 AC: 5485 AN: 33478

American (AMR) AF: 0.0239 AC: 1070 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 430 AN: 26134

East Asian (EAS) AF: 0.156 AC: 6211 AN: 39700

South Asian (SAS) AF: 0.0451 AC: 3890 AN: 86254

European-Finnish (FIN) AF: 0.0643 AC: 3429 AN: 53348

Middle Eastern (MID) AF: 0.0315 AC: 181 AN: 5744

European-Non Finnish (NFE) AF: 0.0507 AC: 56326 AN: 1111854

Other (OTH) AF: 0.0575 AC: 3473 AN: 60374

GnomAD4 genome AF: 0.0834 AC: 12705 AN: 152258 Hom.: 730 Cov.: 33 AF XY: 0.0833 AC XY: 6202 AN XY: 74454

African (AFR) AF: 0.160 AC: 6626 AN: 41522

American (AMR) AF: 0.0385 AC: 590 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.169 AC: 873 AN: 5164

South Asian (SAS) AF: 0.0487 AC: 235 AN: 4828

European-Finnish (FIN) AF: 0.0663 AC: 704 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0505 AC: 3433 AN: 68024

Other (OTH) AF: 0.0624 AC: 132 AN: 2116

Alfa AF: 0.0606 Hom.: 212

Bravo AF: 0.0840

Asia WGS AF: 0.124 AC: 430 AN: 3478

EpiCase AF: 0.0435

EpiControl AF: 0.0438

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

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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 13, 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
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.015
DANN	Benign	0.56
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.012
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: rs73346359; hg19: chr17-6364881; COSMIC: COSV52593002;