17-6461433-A-T

Variant names:

• chr17-6461433-A-T
• rs11654099
• NM_031220.4:c.2430T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031220.4(PITPNM3):​c.2430T>A​(p.Asp810Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 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. Synonymous variant affecting the same amino acid position (i.e. D810D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PITPNM3 NM_031220.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITPNM3	NM_031220.4	c.2430T>A	p.Asp810Glu	missense_variant	Exon 18 of 20	ENST00000262483.13	NP_112497.2
PITPNM3	NM_001165966.2	c.2322T>A	p.Asp774Glu	missense_variant	Exon 17 of 19		NP_001159438.1
PITPNM3	XM_011524015.4	c.2430T>A	p.Asp810Glu	missense_variant	Exon 18 of 19		XP_011522317.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM3	ENST00000262483.13	c.2430T>A	p.Asp810Glu	missense_variant	Exon 18 of 20	1	NM_031220.4	ENSP00000262483.8

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251410 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135892

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 79 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.1
DANN	Benign	0.97
DEOGEN2	Benign	0.29	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.066	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.22
Sift	Benign	0.14	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0060	.;B
Vest4		0.21
MutPred		0.67		.;Gain of relative solvent accessibility (P = 0.09);
MVP		0.28
MPC		0.64
ClinPred		0.14	T
GERP RS		-7.0
Varity_R		0.28
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -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;