7-95308134-T-G

Variant names:

• chr7-95308134-T-G
• rs662
• NM_000446.7:c.575A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000446.7(PON1):​c.575A>C​(p.Gln192Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q192R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PON1 NM_000446.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.954
• Publications: 1187 publications found

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]

PON1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102825135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000446.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.575A>C	p.Gln192Pro	missense	Exon 6 of 9	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.575A>C	p.Gln192Pro	missense	Exon 6 of 9	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.*300A>C		non_coding_transcript_exon	Exon 6 of 9	ENSP00000407359.1
	PON1	ENST00000433729.1	TSL:3	n.*300A>C		3_prime_UTR	Exon 6 of 9	ENSP00000407359.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 44475

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.97
DANN	Benign	0.92
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L
PhyloP100		-0.95
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.019
Sift	Benign	0.043	D
Sift4G	Benign	0.083	T
Polyphen		0.021	B
Vest4		0.15
MutPred		0.51		Loss of catalytic residue at Q192 (P = 0.012)
MVP		0.19
MPC		0.21
ClinPred		0.25	T
GERP RS		-1.0
Varity_R		0.22
gMVP		0.92
Mutation Taster		=84/16	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: rs662; hg19: chr7-94937446;