chr7-95322257-T-C

Variant names:

• chr7-95322257-T-C
• rs3917478
• NM_000446.7:c.74+2145A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000446.7(PON1):​c.74+2145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 128,478 control chromosomes in the GnomAD database, including 830 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (830 hom., cov: 31)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.74+2145A>G		intron_variant	Intron 1 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.74+2145A>G		intron_variant	Intron 1 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.74+2145A>G		intron_variant	Intron 1 of 8	3		ENSP00000407359.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 14756 AN: 128436 Hom.: 830 Cov.: 31

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.0751

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0600

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.109

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.115 AC: 14760 AN: 128478 Hom.: 830 Cov.: 31 AF XY: 0.116 AC XY: 7122 AN XY: 61610

African (AFR) AF: 0.0784 AC: 2930 AN: 37390

American (AMR) AF: 0.0867 AC: 932 AN: 10750

Ashkenazi Jewish (ASJ) AF: 0.0751 AC: 227 AN: 3024

East Asian (EAS) AF: 0.220 AC: 958 AN: 4346

South Asian (SAS) AF: 0.123 AC: 458 AN: 3732

European-Finnish (FIN) AF: 0.144 AC: 1028 AN: 7160

Middle Eastern (MID) AF: 0.0664 AC: 15 AN: 226

European-Non Finnish (NFE) AF: 0.134 AC: 7954 AN: 59414

Other (OTH) AF: 0.107 AC: 175 AN: 1628

Alfa AF: 0.109 Hom.: 1849

Bravo AF: 0.0932

Asia WGS AF: 0.148 AC: 514 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.5
DANN	Benign	0.46
PhyloP100		0.025
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: rs3917478; hg19: chr7-94951569;