NM_031220.4:c.238G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.07

Publications

32 publications found

Variant links:

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

PITPNM3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031220.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITPNM3	NM_031220.4	MANE Select	c.238G>A	p.Ala80Thr	missense	Exon 4 of 20	NP_112497.2	Q9BZ71-1
	PITPNM3	NM_001165966.2		c.130G>A	p.Ala44Thr	missense	Exon 3 of 19	NP_001159438.1	Q9BZ71-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITPNM3	ENST00000262483.13	TSL:1 MANE Select	c.238G>A	p.Ala80Thr	missense	Exon 4 of 20	ENSP00000262483.8	Q9BZ71-1
	PITPNM3	ENST00000421306.7	TSL:2	c.130G>A	p.Ala44Thr	missense	Exon 3 of 19	ENSP00000407882.3	Q9BZ71-3

Frequencies

GnomAD3 genomes

AF:

0.305

AC:

46298

AN:

151932

Hom.:

7123

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.309

AC XY:

224231

AN XY:

725242

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

17468

34936

52403

69871

87339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11466

22932

34398

45864

57330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.305

AC:

46324

AN:

152050

Hom.:

7128

Cov.:

AF XY:

0.301

AC XY:

22376

AN XY:

74302

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1679

3357

5036

6714

8393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cone-rod dystrophy 5 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.24

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.013

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0096

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.11

PhyloP100

-1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

0.63

REVEL

Benign

0.0090

Sift

Benign

0.78

Sift4G

Benign

0.62

Polyphen

0.0020

Vest4

0.058

MPC

0.45

ClinPred

0.0019

GERP RS

-1.6

Varity_R

0.022

gMVP

0.13

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over