rs77580616

chr17-6477223-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031220.4(PITPNM3):c.901-10G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,364 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (75 hom., cov: 32)
  • Exomes 𝑓: 0.013 (706 hom.)
• Consequence: PITPNM3 NM_031220.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000008068
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-6477223-C-G is Benign according to our data. Variant chr17-6477223-C-G is described in ClinVar as [Benign]. Clinvar id is 96202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITPNM3	NM_031220.4	c.901-10G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262483.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITPNM3	ENST00000262483.13	c.901-10G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_031220.4	P1
PITPNM3	ENST00000572795.1	n.3407-10G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
PITPNM3	ENST00000421306.7	c.793-10G>C		splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1808 AN: 152064 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0417

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00685

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0214 AC: 5379 AN: 250910 Hom.: 251 AF XY: 0.0221 AC XY: 2993 AN XY: 135732

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00755

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.0388

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00699

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0126 AC: 18348 AN: 1461182 Hom.: 706 Cov.: 31 AF XY: 0.0132 AC XY: 9617 AN XY: 726950

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00930

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.0354

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.00598

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.0119 AC: 1810 AN: 152182 Hom.: 75 Cov.: 32 AF XY: 0.0135 AC XY: 1004 AN XY: 74390

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.0418

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.00685

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00909 Hom.: 4

Bravo AF: 0.0105

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -

Cone-rod dystrophy 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.79
Cadd	Benign	11
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000081
dbscSNV1_RF	Benign	0.0
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: rs77580616; hg19: chr17-6380543; COSMIC: COSV52593841; COSMIC: COSV52593841;