7-95315611-C-T

Variant names:

• chr7-95315611-C-T
• rs854556
• NM_000446.7:c.202-121G>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.202-121G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,019,712 control chromosomes in the GnomAD database, including 56,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7020 hom., cov: 32)
  • Exomes 𝑓: 0.32 (49175 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.15
• Publications: 8 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 7-95315611-C-T is Benign according to our data. Variant chr7-95315611-C-T is described in ClinVar as Benign. ClinVar VariationId is 1242106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	NM_000446.7	MANE Select	c.202-121G>A		intron	N/A	NP_000437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PON1	ENST00000222381.8	TSL:1 MANE Select	c.202-121G>A		intron	N/A	ENSP00000222381.3
	PON1	ENST00000433729.1	TSL:3	n.202-162G>A		intron	N/A	ENSP00000407359.1
	PON1	ENST00000470502.1	TSL:4	n.322-121G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43659 AN: 151936 Hom.: 7017 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.0355

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.319

GnomAD4 exome AF: 0.323 AC: 280538 AN: 867658 Hom.: 49175 AF XY: 0.321 AC XY: 144504 AN XY: 449906

African (AFR) AF: 0.168 AC: 3644 AN: 21662

American (AMR) AF: 0.216 AC: 7818 AN: 36264

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 8694 AN: 21766

East Asian (EAS) AF: 0.0615 AC: 2130 AN: 34628

South Asian (SAS) AF: 0.211 AC: 14833 AN: 70246

European-Finnish (FIN) AF: 0.364 AC: 13318 AN: 36632

Middle Eastern (MID) AF: 0.381 AC: 1781 AN: 4670

European-Non Finnish (NFE) AF: 0.358 AC: 215320 AN: 600984

Other (OTH) AF: 0.319 AC: 13000 AN: 40806

GnomAD4 genome AF: 0.287 AC: 43671 AN: 152054 Hom.: 7020 Cov.: 32 AF XY: 0.284 AC XY: 21077 AN XY: 74330

African (AFR) AF: 0.176 AC: 7288 AN: 41484

American (AMR) AF: 0.273 AC: 4176 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1378 AN: 3472

East Asian (EAS) AF: 0.0358 AC: 185 AN: 5174

South Asian (SAS) AF: 0.202 AC: 972 AN: 4820

European-Finnish (FIN) AF: 0.350 AC: 3695 AN: 10566

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24870 AN: 67938

Other (OTH) AF: 0.316 AC: 666 AN: 2110

Alfa AF: 0.335 Hom.: 11290

Bravo AF: 0.277

Asia WGS AF: 0.118 AC: 415 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.8
DANN	Benign	0.73
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs854556; hg19: chr7-94944923; COSMIC: COSV55931023;