rs75323938

Variant names:

• chr17-6464150-G-A
• rs75323938
• NM_031220.4:c.2156+20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031220.4(PITPNM3):​c.2156+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,614,096 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (14 hom., cov: 33)
  • Exomes 𝑓: 0.016 (213 hom.)
• Consequence: PITPNM3 NM_031220.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.505
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-6464150-G-A is Benign according to our data. Variant chr17-6464150-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00958 (1458/152266) while in subpopulation NFE AF = 0.0165 (1120/68010). AF 95% confidence interval is 0.0157. There are 14 homozygotes in GnomAd4. There are 634 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1458 AD gene.

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.2156+20C>T		intron	N/A	NP_112497.2	Q9BZ71-1
	PITPNM3	NM_001165966.2		c.2048+20C>T		intron	N/A	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.2156+20C>T		intron	N/A	ENSP00000262483.8	Q9BZ71-1
	PITPNM3	ENST00000572795.1	TSL:1	n.4662+20C>T		intron	N/A
	PITPNM3	ENST00000576664.5	TSL:1	n.905+20C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1457 AN: 152148 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00838 AC: 2096 AN: 250086 AF XY: 0.00857

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00851

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.0156 AC: 22802 AN: 1461830 Hom.: 213 Cov.: 33 AF XY: 0.0152 AC XY: 11040 AN XY: 727220

African (AFR) AF: 0.00251 AC: 84 AN: 33480

American (AMR) AF: 0.00284 AC: 127 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00497 AC: 130 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00148 AC: 128 AN: 86242

European-Finnish (FIN) AF: 0.00854 AC: 456 AN: 53400

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0189 AC: 20993 AN: 1111988

Other (OTH) AF: 0.0145 AC: 874 AN: 60394

GnomAD4 genome AF: 0.00958 AC: 1458 AN: 152266 Hom.: 14 Cov.: 33 AF XY: 0.00852 AC XY: 634 AN XY: 74442

African (AFR) AF: 0.00344 AC: 143 AN: 41548

American (AMR) AF: 0.00314 AC: 48 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.00753 AC: 80 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0165 AC: 1120 AN: 68010

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0133 Hom.: 2

Bravo AF: 0.00941

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.60
PhyloP100		0.51
PromoterAI		0.052	Neutral
Mutation Taster		=100/0	polymorphism

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: rs75323938; hg19: chr17-6367470;