Genetic Variant PITPNM2:p.Arg1320Leu (chr12-122986118-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020845.3(PITPNM2):c.3959G>T(p.Arg1320Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,350,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1320P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

PITPNM2
NM_020845.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.52

Publications

0 publications found

Variant links:

Genes affected

PITPNM2 (HGNC:21044): (phosphatidylinositol transfer protein membrane associated 2) PITPNM2 belongs to a family of membrane-associated phosphatidylinositol transfer domain-containing proteins that share homology with the Drosophila retinal degeneration B (rdgB) protein (Ocaka et al., 2005 [PubMed 15627748]).[supplied by OMIM, Mar 2008]

PITPNM2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22237158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITPNM2	NM_020845.3 link	c.3959G>T	p.Arg1320Leu	missense_variant	Exon 26 of 26	ENST00000320201.10	NP_065896.1	Q9BZ72-1Q9UF51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM2	ENST00000320201.10 link	c.3959G>T	p.Arg1320Leu	missense_variant	Exon 26 of 26	5	NM_020845.3	ENSP00000322218.4		Q9BZ72-1
PITPNM2	ENST00000280562.9 link	c.3941G>T	p.Arg1314Leu	missense_variant	Exon 25 of 25	5		ENSP00000280562.5		Q9BZ72-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

102530

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.41e-7

AC:

AN:

1350110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

665004

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000360

AC:

AN:

27746

American (AMR)

AF:

0.00

AC:

AN:

30746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23716

East Asian (EAS)

AF:

0.00

AC:

AN:

32700

South Asian (SAS)

AF:

0.00

AC:

AN:

75202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4442

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1064998

Other (OTH)

AF:

0.00

AC:

AN:

56168

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.9

L;.;L

PhyloP100

2.5

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.049

D;D;D

Sift4G

Benign

0.22

T;T;T

Polyphen

0.53

P;P;P

Vest4

0.30

MutPred

0.33

Gain of catalytic residue at R1320 (P = 0.0077);.;Gain of catalytic residue at R1320 (P = 0.0077);

MVP

0.44

MPC

2.4

ClinPred

0.93

GERP RS

4.8

Varity_R

0.21

gMVP

0.43

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over