chr12-122986298-C-A

Variant names:

• chr12-122986298-C-A
• rs150792674
• NM_020845.3:c.3779G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020845.3(PITPNM2):​c.3779G>T​(p.Arg1260Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,430,170 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. R1260Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PITPNM2 NM_020845.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.12
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26944363).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020845.3. 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
	PITPNM2	NM_020845.3	MANE Select	c.3779G>T	p.Arg1260Leu	missense	Exon 26 of 26	NP_065896.1	Q9BZ72-1
	PITPNM2	NM_001384660.1		c.3956G>T	p.Arg1319Leu	missense	Exon 26 of 26	NP_001371589.1
	PITPNM2	NM_001300801.2		c.3761G>T	p.Arg1254Leu	missense	Exon 26 of 26	NP_001287730.1	Q9BZ72-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITPNM2	ENST00000320201.10	TSL:5 MANE Select	c.3779G>T	p.Arg1260Leu	missense	Exon 26 of 26	ENSP00000322218.4	Q9BZ72-1
	PITPNM2	ENST00000876870.1		c.3779G>T	p.Arg1260Leu	missense	Exon 25 of 25	ENSP00000546929.1
	PITPNM2	ENST00000280562.9	TSL:5	c.3761G>T	p.Arg1254Leu	missense	Exon 25 of 25	ENSP00000280562.5	Q9BZ72-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430170 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709036

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

African (AFR) AF: 0.00 AC: 0 AN: 32840

American (AMR) AF: 0.00 AC: 0 AN: 40276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25110

East Asian (EAS) AF: 0.00 AC: 0 AN: 38640

South Asian (SAS) AF: 0.00 AC: 0 AN: 82286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099736

Other (OTH) AF: 0.00 AC: 0 AN: 59110

⚠️ 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.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Benign	0.90
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.25
Sift	Benign	0.72	T
Sift4G	Benign	0.84	T
Polyphen		1.0	D
Vest4		0.45
MutPred		0.39		Loss of solvent accessibility (P = 0.0052)
MVP		0.25
MPC		2.4
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.25
gMVP		0.64
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs150792674; hg19: chr12-123470845;