rs149964592

Variant names:

• chr17-6478625-G-A
• rs149964592
• NM_031220.4:c.699C>T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_031220.4(PITPNM3):​c.699C>T​(p.Val233Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00895 in 1,614,006 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (85 hom.)
• Consequence: PITPNM3 NM_031220.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.70

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-6478625-G-A is Benign according to our data. Variant chr17-6478625-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6478625-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BS2: High AC in GnomAd4 at 1052 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITPNM3	NM_031220.4	c.699C>T	p.Val233Val	synonymous_variant	Exon 7 of 20	ENST00000262483.13	NP_112497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM3	ENST00000262483.13	c.699C>T	p.Val233Val	synonymous_variant	Exon 7 of 20	1	NM_031220.4	ENSP00000262483.8
PITPNM3	ENST00000572795.1	n.3205C>T		non_coding_transcript_exon_variant	Exon 1 of 14	1
PITPNM3	ENST00000421306.7	c.591C>T	p.Val197Val	synonymous_variant	Exon 6 of 19	2		ENSP00000407882.3

Frequencies

GnomAD3 genomes AF: 0.00692 AC: 1053 AN: 152150 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00983

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00778 AC: 1950 AN: 250582 Hom.: 16 AF XY: 0.00787 AC XY: 1067 AN XY: 135656

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00848

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.00916 AC: 13388 AN: 1461738 Hom.: 85 Cov.: 33 AF XY: 0.00900 AC XY: 6541 AN XY: 727160

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00875

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.00283

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.00835

GnomAD4 genome AF: 0.00691 AC: 1052 AN: 152268 Hom.: 2 Cov.: 32 AF XY: 0.00670 AC XY: 499 AN XY: 74450

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00983

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00919 Hom.: 2

Bravo AF: 0.00828

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PITPNM3: BP4, BP7, BS1, BS2 -

Cone-rod dystrophy 5 Benign:2

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. -

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.75

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

Other links and lift over

dbSNP: rs149964592; hg19: chr17-6381945; COSMIC: COSV52592846;