17-6483627-G-A

Variant names:

• chr17-6483627-G-A
• rs34897053
• NM_031220.4:c.477C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031220.4(PITPNM3):​c.477C>T​(p.Ser159Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 1,614,062 control chromosomes in the GnomAD database, including 1,644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S159S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (142 hom., cov: 31)
  • Exomes 𝑓: 0.033 (1502 hom.)
• Consequence: PITPNM3 NM_031220.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.51
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 17-6483627-G-A is Benign according to our data. Variant chr17-6483627-G-A is described in ClinVar as Benign. ClinVar VariationId is 261948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.123 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.477C>T	p.Ser159Ser	synonymous	Exon 6 of 20	NP_112497.2	Q9BZ71-1
	PITPNM3	NM_001165966.2		c.369C>T	p.Ser123Ser	synonymous	Exon 5 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.477C>T	p.Ser159Ser	synonymous	Exon 6 of 20	ENSP00000262483.8	Q9BZ71-1
	PITPNM3	ENST00000421306.7	TSL:2	c.369C>T	p.Ser123Ser	synonymous	Exon 5 of 19	ENSP00000407882.3	Q9BZ71-3

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4583 AN: 152058 Hom.: 140 Cov.: 31

Gnomad AFR AF: 0.00891

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0780

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.0623

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0413

GnomAD2 exomes AF: 0.0499 AC: 12539 AN: 251264 AF XY: 0.0519

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.0669

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0491

GnomAD4 exome AF: 0.0330 AC: 48215 AN: 1461886 Hom.: 1502 Cov.: 32 AF XY: 0.0354 AC XY: 25745 AN XY: 727246

African (AFR) AF: 0.00863 AC: 289 AN: 33480

American (AMR) AF: 0.105 AC: 4687 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0388 AC: 1014 AN: 26136

East Asian (EAS) AF: 0.0562 AC: 2232 AN: 39700

South Asian (SAS) AF: 0.118 AC: 10153 AN: 86258

European-Finnish (FIN) AF: 0.0228 AC: 1217 AN: 53420

Middle Eastern (MID) AF: 0.0758 AC: 437 AN: 5768

European-Non Finnish (NFE) AF: 0.0231 AC: 25736 AN: 1112006

Other (OTH) AF: 0.0406 AC: 2450 AN: 60396

GnomAD4 genome AF: 0.0301 AC: 4586 AN: 152176 Hom.: 142 Cov.: 31 AF XY: 0.0325 AC XY: 2415 AN XY: 74416

African (AFR) AF: 0.00888 AC: 369 AN: 41532

American (AMR) AF: 0.0781 AC: 1194 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3468

East Asian (EAS) AF: 0.0614 AC: 316 AN: 5144

South Asian (SAS) AF: 0.131 AC: 631 AN: 4812

European-Finnish (FIN) AF: 0.0240 AC: 254 AN: 10602

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1568 AN: 68016

Other (OTH) AF: 0.0437 AC: 92 AN: 2104

Alfa AF: 0.0180 Hom.: 18

Bravo AF: 0.0330

Asia WGS AF: 0.110 AC: 382 AN: 3478

EpiCase AF: 0.0244

EpiControl AF: 0.0260

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cone-rod dystrophy 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.98
DANN	Benign	0.70
PhyloP100		-4.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs34897053; hg19: chr17-6386947; COSMIC: COSV52598343; COSMIC: COSV52598343;