chr7-95318657-C-T

Variant names:

• chr7-95318657-C-T
• rs854562
• NM_000446.7:c.75-264G>A

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.75-264G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 396,058 control chromosomes in the GnomAD database, including 15,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5234 hom., cov: 32)
  • Exomes 𝑓: 0.28 (10655 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.209
• Publications: 10 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=-0.81).
• BP6: Variant 7-95318657-C-T is Benign according to our data. Variant chr7-95318657-C-T is described in ClinVar as Benign. ClinVar VariationId is 1284201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.32 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.75-264G>A		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.75-264G>A		intron	N/A	ENSP00000222381.3	P27169
	PON1	ENST00000893040.1		c.75-264G>A		intron	N/A	ENSP00000563099.1
	PON1	ENST00000893036.1		c.75-264G>A		intron	N/A	ENSP00000563095.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35890 AN: 151926 Hom.: 5234 Cov.: 32

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.0351

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.271

GnomAD4 exome AF: 0.281 AC: 68649 AN: 244014 Hom.: 10655 AF XY: 0.277 AC XY: 36219 AN XY: 130798

African (AFR) AF: 0.0801 AC: 594 AN: 7414

American (AMR) AF: 0.215 AC: 2469 AN: 11476

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 2727 AN: 6802

East Asian (EAS) AF: 0.0533 AC: 752 AN: 14108

South Asian (SAS) AF: 0.212 AC: 7240 AN: 34092

European-Finnish (FIN) AF: 0.320 AC: 3826 AN: 11948

Middle Eastern (MID) AF: 0.343 AC: 349 AN: 1018

European-Non Finnish (NFE) AF: 0.325 AC: 46748 AN: 143736

Other (OTH) AF: 0.294 AC: 3944 AN: 13420

GnomAD4 genome AF: 0.236 AC: 35889 AN: 152044 Hom.: 5234 Cov.: 32 AF XY: 0.235 AC XY: 17433 AN XY: 74304

African (AFR) AF: 0.0838 AC: 3477 AN: 41496

American (AMR) AF: 0.240 AC: 3665 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1369 AN: 3472

East Asian (EAS) AF: 0.0354 AC: 183 AN: 5172

South Asian (SAS) AF: 0.199 AC: 961 AN: 4822

European-Finnish (FIN) AF: 0.312 AC: 3290 AN: 10536

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.323 AC: 21976 AN: 67958

Other (OTH) AF: 0.269 AC: 567 AN: 2108

Alfa AF: 0.291 Hom.: 22870

Bravo AF: 0.224

Asia WGS AF: 0.111 AC: 388 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	-0.81
CADD	Benign	9.7
DANN	Benign	0.60
PhyloP100		0.21
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: rs854562; hg19: chr7-94947969;