chr7-95318487-G-A

Variant names:

• chr7-95318487-G-A
• rs2074351
• NM_000446.7:c.75-94C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000446.7(PON1):​c.75-94C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,156,122 control chromosomes in the GnomAD database, including 49,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5592 hom., cov: 32)
  • Exomes 𝑓: 0.29 (44376 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-95318487-G-A is Benign according to our data. Variant chr7-95318487-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.75-94C>T		intron	N/A	NP_000437.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.75-94C>T		intron	N/A	ENSP00000222381.3	P27169
	PON1	ENST00000893040.1		c.75-94C>T		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.75-94C>T		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39961 AN: 151976 Hom.: 5585 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.289 AC: 290159 AN: 1004028 Hom.: 44376 Cov.: 13 AF XY: 0.290 AC XY: 149711 AN XY: 517118

African (AFR) AF: 0.177 AC: 4335 AN: 24430

American (AMR) AF: 0.306 AC: 12486 AN: 40780

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 6055 AN: 22418

East Asian (EAS) AF: 0.548 AC: 20117 AN: 36734

South Asian (SAS) AF: 0.310 AC: 23296 AN: 75110

European-Finnish (FIN) AF: 0.248 AC: 10619 AN: 42760

Middle Eastern (MID) AF: 0.220 AC: 1061 AN: 4826

European-Non Finnish (NFE) AF: 0.280 AC: 199411 AN: 711936

Other (OTH) AF: 0.284 AC: 12779 AN: 45034

GnomAD4 genome AF: 0.263 AC: 39990 AN: 152094 Hom.: 5592 Cov.: 32 AF XY: 0.266 AC XY: 19779 AN XY: 74352

African (AFR) AF: 0.178 AC: 7396 AN: 41482

American (AMR) AF: 0.292 AC: 4466 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 987 AN: 3472

East Asian (EAS) AF: 0.525 AC: 2715 AN: 5174

South Asian (SAS) AF: 0.322 AC: 1555 AN: 4826

European-Finnish (FIN) AF: 0.264 AC: 2790 AN: 10560

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19110 AN: 67990

Other (OTH) AF: 0.286 AC: 603 AN: 2110

Alfa AF: 0.276 Hom.: 8531

Bravo AF: 0.264

Asia WGS AF: 0.430 AC: 1495 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.6
DANN	Benign	0.50
PhyloP100		0.063
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: rs2074351; hg19: chr7-94947799; COSMIC: COSV55931030;