NM_031220.4:c.2430T>C

Variant names:

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

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.2430T>C​(p.Asp810Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 1,614,072 control chromosomes in the GnomAD database, including 592,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60029 hom., cov: 35)
  • Exomes 𝑓: 0.85 (532636 hom.)
• Consequence: PITPNM3 NM_031220.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.25
• Publications: 20 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=-0.81).
• BP6: Variant 17-6461433-A-G is Benign according to our data. Variant chr17-6461433-A-G is described in ClinVar as Benign. ClinVar VariationId is 261946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.962 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.2430T>C	p.Asp810Asp	synonymous	Exon 18 of 20	NP_112497.2
	PITPNM3	NM_001165966.2		c.2322T>C	p.Asp774Asp	synonymous	Exon 17 of 19	NP_001159438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITPNM3	ENST00000262483.13	TSL:1 MANE Select	c.2430T>C	p.Asp810Asp	synonymous	Exon 18 of 20	ENSP00000262483.8
	PITPNM3	ENST00000572795.1	TSL:1	n.4936T>C		non_coding_transcript_exon	Exon 12 of 14
	PITPNM3	ENST00000576664.5	TSL:1	n.1179T>C		non_coding_transcript_exon	Exon 9 of 11

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134755 AN: 152186 Hom.: 59962 Cov.: 35

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.936

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.887

GnomAD2 exomes AF: 0.866 AC: 217761 AN: 251410 AF XY: 0.866

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.906

Gnomad EAS exome AF: 0.906

Gnomad FIN exome AF: 0.818

Gnomad NFE exome AF: 0.848

Gnomad OTH exome AF: 0.870

GnomAD4 exome AF: 0.853 AC: 1246719 AN: 1461768 Hom.: 532636 Cov.: 79 AF XY: 0.854 AC XY: 620769 AN XY: 727190

African (AFR) AF: 0.977 AC: 32704 AN: 33480

American (AMR) AF: 0.852 AC: 38108 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 23594 AN: 26136

East Asian (EAS) AF: 0.927 AC: 36817 AN: 39700

South Asian (SAS) AF: 0.880 AC: 75937 AN: 86256

European-Finnish (FIN) AF: 0.820 AC: 43726 AN: 53352

Middle Eastern (MID) AF: 0.915 AC: 5276 AN: 5768

European-Non Finnish (NFE) AF: 0.844 AC: 938088 AN: 1111958

Other (OTH) AF: 0.869 AC: 52469 AN: 60396

GnomAD4 genome AF: 0.886 AC: 134882 AN: 152304 Hom.: 60029 Cov.: 35 AF XY: 0.885 AC XY: 65887 AN XY: 74460

African (AFR) AF: 0.970 AC: 40347 AN: 41584

American (AMR) AF: 0.855 AC: 13082 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3139 AN: 3472

East Asian (EAS) AF: 0.910 AC: 4701 AN: 5168

South Asian (SAS) AF: 0.889 AC: 4296 AN: 4830

European-Finnish (FIN) AF: 0.816 AC: 8664 AN: 10614

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.847 AC: 57642 AN: 68020

Other (OTH) AF: 0.889 AC: 1874 AN: 2108

Alfa AF: 0.866 Hom.: 82452

Bravo AF: 0.894

Asia WGS AF: 0.906 AC: 3151 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Cone-rod dystrophy 5 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.22
DANN	Benign	0.51
PhyloP100		-1.3
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: rs11654099; hg19: chr17-6364753; COSMIC: COSV52598333;