chr17-6478619-G-A

Position:

• chr17-6478619-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031220.4(PITPNM3):​c.705C>T​(p.Thr235Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,613,450 control chromosomes in the GnomAD database, including 281,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21195 hom., cov: 32)
  • Exomes 𝑓: 0.59 (260248 hom.)
• Consequence: PITPNM3 NM_031220.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.38

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-6478619-G-A is Benign according to our data. Variant chr17-6478619-G-A is described in ClinVar as [Benign]. Clinvar id is 261951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITPNM3	NM_031220.4	c.705C>T	p.Thr235Thr	synonymous_variant	7/20	ENST00000262483.13	NP_112497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITPNM3	ENST00000262483.13	c.705C>T	p.Thr235Thr	synonymous_variant	7/20	1	NM_031220.4	ENSP00000262483.8
PITPNM3	ENST00000572795.1	n.3211C>T		non_coding_transcript_exon_variant	1/14	1
PITPNM3	ENST00000421306.7	c.597C>T	p.Thr199Thr	synonymous_variant	6/19	2		ENSP00000407882.3

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76724 AN: 151920 Hom.: 21194 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.556

GnomAD3 exomes AF: 0.530 AC: 132573 AN: 250108 Hom.: 37202 AF XY: 0.536 AC XY: 72508 AN XY: 135396

Gnomad AFR exome AF: 0.280

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.615

Gnomad EAS exome AF: 0.254

Gnomad SAS exome AF: 0.429

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.577

GnomAD4 exome AF: 0.589 AC: 860742 AN: 1461412 Hom.: 260248 Cov.: 67 AF XY: 0.587 AC XY: 426430 AN XY: 726978

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.613

Gnomad4 EAS exome AF: 0.230

Gnomad4 SAS exome AF: 0.436

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.626

Gnomad4 OTH exome AF: 0.569

GnomAD4 genome AF: 0.505 AC: 76730 AN: 152038 Hom.: 21195 Cov.: 32 AF XY: 0.503 AC XY: 37357 AN XY: 74286

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.533

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.619

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.551

Alfa AF: 0.605 Hom.: 42951

Bravo AF: 0.490

Asia WGS AF: 0.340 AC: 1187 AN: 3478

EpiCase AF: 0.644

EpiControl AF: 0.641

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cone-rod dystrophy 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.069
DANN	Benign	0.78

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

LitVar

Other links and lift over

dbSNP: rs938288; hg19: chr17-6381939; COSMIC: COSV52595054;