7-95306305-A-G

Position:

• chr7-95306305-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000446.7(PON1):​c.760T>C​(p.Trp254Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PON1 NM_000446.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

Genes affected

PON1 (HGNC:9204): (paraoxonase 1) This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PON1	NM_000446.7	c.760T>C	p.Trp254Arg	missense_variant	7/9	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.760T>C	p.Trp254Arg	missense_variant	7/9	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*485T>C		non_coding_transcript_exon_variant	7/9	3		ENSP00000407359.1
PON1	ENST00000433729.1	n.*485T>C		3_prime_UTR_variant	7/9	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2024

The c.760T>C (p.W254R) alteration is located in exon 7 (coding exon 7) of the PON1 gene. This alteration results from a T to C substitution at nucleotide position 760, causing the tryptophan (W) at amino acid position 254 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.023
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.24
Sift	Benign	0.39	T
Sift4G	Benign	0.35	T
Polyphen		0.014	B
Vest4		0.63
MutPred		0.64		Gain of disorder (P = 0.0102);
MVP		0.53
MPC		0.80
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.32
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-94935617; COSMIC: COSV55933304; COSMIC: COSV55933304;