rs3809835

Variant names:

• chr17-6503563-C-T
• rs3809835
• NM_031220.4:c.238G>A

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.238G>A​(p.Ala80Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,609,844 control chromosomes in the GnomAD database, including 78,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. A80V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (7128 hom., cov: 32)
  • Exomes 𝑓: 0.31 (71846 hom.)
• Consequence: PITPNM3 NM_031220.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.07
• Publications: 32 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=0.008624226).
• BP6: Variant 17-6503563-C-T is Benign according to our data. Variant chr17-6503563-C-T is described in ClinVar as Benign. ClinVar VariationId is 261945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITPNM3	NM_031220.4	c.238G>A	p.Ala80Thr	missense_variant	Exon 4 of 20	ENST00000262483.13	NP_112497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM3	ENST00000262483.13	c.238G>A	p.Ala80Thr	missense_variant	Exon 4 of 20	1	NM_031220.4	ENSP00000262483.8
PITPNM3	ENST00000421306.7	c.130G>A	p.Ala44Thr	missense_variant	Exon 3 of 19	2		ENSP00000407882.3

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46298 AN: 151932 Hom.: 7123 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.283 AC: 69696 AN: 246648 AF XY: 0.287

Gnomad AFR exome AF: 0.285

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.257

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.301

GnomAD4 exome AF: 0.310 AC: 452517 AN: 1457794 Hom.: 71846 Cov.: 42 AF XY: 0.309 AC XY: 224231 AN XY: 725242

African (AFR) AF: 0.287 AC: 9612 AN: 33460

American (AMR) AF: 0.180 AC: 8051 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 9424 AN: 26124

East Asian (EAS) AF: 0.244 AC: 9676 AN: 39694

South Asian (SAS) AF: 0.230 AC: 19856 AN: 86208

European-Finnish (FIN) AF: 0.298 AC: 15033 AN: 50412

Middle Eastern (MID) AF: 0.359 AC: 2048 AN: 5700

European-Non Finnish (NFE) AF: 0.324 AC: 359738 AN: 1111146

Other (OTH) AF: 0.316 AC: 19079 AN: 60338

GnomAD4 genome AF: 0.305 AC: 46324 AN: 152050 Hom.: 7128 Cov.: 32 AF XY: 0.301 AC XY: 22376 AN XY: 74302

African (AFR) AF: 0.283 AC: 11720 AN: 41484

American (AMR) AF: 0.263 AC: 4013 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1260 AN: 3466

East Asian (EAS) AF: 0.257 AC: 1327 AN: 5154

South Asian (SAS) AF: 0.225 AC: 1083 AN: 4822

European-Finnish (FIN) AF: 0.306 AC: 3234 AN: 10578

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22570 AN: 67950

Other (OTH) AF: 0.319 AC: 672 AN: 2108

Alfa AF: 0.320 Hom.: 31940

Bravo AF: 0.298

TwinsUK AF: 0.334 AC: 1237

ALSPAC AF: 0.325 AC: 1251

ESP6500AA AF: 0.278 AC: 1224

ESP6500EA AF: 0.336 AC: 2890

ExAC AF: 0.283 AC: 34417

Asia WGS AF: 0.215 AC: 751 AN: 3476

EpiCase AF: 0.352

EpiControl AF: 0.352

ClinVar

Significance: 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

- -

Apr 26, 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

- -

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 05, 2021

Genome-Nilou Lab

Significance: 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
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.24
DANN	Benign	0.87
DEOGEN2	Benign	0.013	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.11	.;N
PhyloP100		-1.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.63	N;N
REVEL	Benign	0.0090
Sift	Benign	0.78	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0020	.;B
Vest4		0.058
MPC		0.45
ClinPred		0.0019	T
GERP RS		-1.6
Varity_R		0.022
gMVP		0.13
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3809835; hg19: chr17-6406883; COSMIC: COSV52593430;