chr17-6478619-G-A

Variant names:

• chr17-6478619-G-A
• rs938288
• NM_031220.4:c.705C>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.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
• Publications: 22 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=-0.76).
• BP6: Variant 17-6478619-G-A is Benign according to our data. Variant chr17-6478619-G-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
PITPNM3	NM_031220.4	c.705C>T	p.Thr235Thr	synonymous_variant	Exon 7 of 20	ENST00000262483.13	NP_112497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM3	ENST00000262483.13	c.705C>T	p.Thr235Thr	synonymous_variant	Exon 7 of 20	1	NM_031220.4	ENSP00000262483.8
PITPNM3	ENST00000572795.1	n.3211C>T		non_coding_transcript_exon_variant	Exon 1 of 14	1
PITPNM3	ENST00000421306.7	c.597C>T	p.Thr199Thr	synonymous_variant	Exon 6 of 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

GnomAD2 exomes AF: 0.530 AC: 132573 AN: 250108 AF XY: 0.536

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 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

African (AFR) AF: 0.280 AC: 9389 AN: 33480

American (AMR) AF: 0.500 AC: 22334 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 16014 AN: 26132

East Asian (EAS) AF: 0.230 AC: 9149 AN: 39694

South Asian (SAS) AF: 0.436 AC: 37635 AN: 86226

European-Finnish (FIN) AF: 0.605 AC: 32244 AN: 53326

Middle Eastern (MID) AF: 0.625 AC: 3603 AN: 5766

European-Non Finnish (NFE) AF: 0.626 AC: 695999 AN: 1111756

Other (OTH) AF: 0.569 AC: 34375 AN: 60378

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

African (AFR) AF: 0.295 AC: 12230 AN: 41460

American (AMR) AF: 0.533 AC: 8147 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2084 AN: 3470

East Asian (EAS) AF: 0.243 AC: 1255 AN: 5162

South Asian (SAS) AF: 0.408 AC: 1965 AN: 4818

European-Finnish (FIN) AF: 0.619 AC: 6544 AN: 10570

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42661 AN: 67956

Other (OTH) AF: 0.551 AC: 1163 AN: 2112

Alfa AF: 0.579 Hom.: 72983

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

Apr 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 5 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.069
DANN	Benign	0.78
PhyloP100		-2.4
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: rs938288; hg19: chr17-6381939; COSMIC: COSV52595054;