rs11654099

Positions:

• chr17-6461433-A-G
• chr17-6461433-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031220.4(PITPNM3):​c.2430T>C​(p.Asp810=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 1,614,072 control chromosomes in the GnomAD database, including 592,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60029 hom., cov: 35)
  • Exomes 𝑓: 0.85 (532636 hom.)
• Consequence: PITPNM3 NM_031220.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.25

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-6461433-A-G is Benign according to our data. Variant chr17-6461433-A-G is described in ClinVar as [Benign]. Clinvar id is 261946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6461433-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITPNM3	NM_031220.4	c.2430T>C	p.Asp810=	synonymous_variant	18/20	ENST00000262483.13
PITPNM3	NM_001165966.2	c.2322T>C	p.Asp774=	synonymous_variant	17/19
PITPNM3	XM_011524015.4	c.2430T>C	p.Asp810=	synonymous_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITPNM3	ENST00000262483.13	c.2430T>C	p.Asp810=	synonymous_variant	18/20	1	NM_031220.4	P1

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134755 AN: 152186 Hom.: 59962 Cov.: 35

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.936

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.887

GnomAD3 exomes AF: 0.866 AC: 217761 AN: 251410 Hom.: 94582 AF XY: 0.866 AC XY: 117668 AN XY: 135892

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.906

Gnomad EAS exome AF: 0.906

Gnomad SAS exome AF: 0.883

Gnomad FIN exome AF: 0.818

Gnomad NFE exome AF: 0.848

Gnomad OTH exome AF: 0.870

GnomAD4 exome AF: 0.853 AC: 1246719 AN: 1461768 Hom.: 532636 Cov.: 79 AF XY: 0.854 AC XY: 620769 AN XY: 727190

Gnomad4 AFR exome AF: 0.977

Gnomad4 AMR exome AF: 0.852

Gnomad4 ASJ exome AF: 0.903

Gnomad4 EAS exome AF: 0.927

Gnomad4 SAS exome AF: 0.880

Gnomad4 FIN exome AF: 0.820

Gnomad4 NFE exome AF: 0.844

Gnomad4 OTH exome AF: 0.869

GnomAD4 genome AF: 0.886 AC: 134882 AN: 152304 Hom.: 60029 Cov.: 35 AF XY: 0.885 AC XY: 65887 AN XY: 74460

Gnomad4 AFR AF: 0.970

Gnomad4 AMR AF: 0.855

Gnomad4 ASJ AF: 0.904

Gnomad4 EAS AF: 0.910

Gnomad4 SAS AF: 0.889

Gnomad4 FIN AF: 0.816

Gnomad4 NFE AF: 0.847

Gnomad4 OTH AF: 0.889

Alfa AF: 0.862 Hom.: 66554

Bravo AF: 0.894

Asia WGS AF: 0.906 AC: 3151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone-rod dystrophy 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.22
DANN	Benign	0.51

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: rs11654099; hg19: chr17-6364753; COSMIC: COSV52598333;