chr7-95311726-G-T

Variant names:

• chr7-95311726-G-T
• rs1157745
• NM_000446.7:c.371-149C>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.371-149C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 854,286 control chromosomes in the GnomAD database, including 58,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15768 hom., cov: 32)
  • Exomes 𝑓: 0.32 (42326 hom.)
• Consequence: PON1 NM_000446.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.142
• 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=-0.59).
• BP6: Variant 7-95311726-G-T is Benign according to our data. Variant chr7-95311726-G-T is described in ClinVar as Benign. ClinVar VariationId is 1260271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PON1	NM_000446.7	c.371-149C>A		intron_variant	Intron 4 of 8	ENST00000222381.8	NP_000437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PON1	ENST00000222381.8	c.371-149C>A		intron_variant	Intron 4 of 8	1	NM_000446.7	ENSP00000222381.3
PON1	ENST00000433729.1	n.*96-149C>A		intron_variant	Intron 4 of 8	3		ENSP00000407359.1
PON1	ENST00000470502.1	n.491-149C>A		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63914 AN: 151902 Hom.: 15723 Cov.: 32

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.399

GnomAD4 exome AF: 0.324 AC: 227757 AN: 702266 Hom.: 42326 AF XY: 0.323 AC XY: 118355 AN XY: 366612

African (AFR) AF: 0.671 AC: 11598 AN: 17280

American (AMR) AF: 0.465 AC: 13452 AN: 28956

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 5572 AN: 18076

East Asian (EAS) AF: 0.656 AC: 21096 AN: 32150

South Asian (SAS) AF: 0.367 AC: 20965 AN: 57116

European-Finnish (FIN) AF: 0.266 AC: 9156 AN: 34368

Middle Eastern (MID) AF: 0.297 AC: 1043 AN: 3510

European-Non Finnish (NFE) AF: 0.279 AC: 133009 AN: 476130

Other (OTH) AF: 0.342 AC: 11866 AN: 34680

GnomAD4 genome AF: 0.421 AC: 64020 AN: 152020 Hom.: 15768 Cov.: 32 AF XY: 0.422 AC XY: 31336 AN XY: 74292

African (AFR) AF: 0.670 AC: 27808 AN: 41476

American (AMR) AF: 0.422 AC: 6450 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1119 AN: 3472

East Asian (EAS) AF: 0.642 AC: 3299 AN: 5138

South Asian (SAS) AF: 0.390 AC: 1876 AN: 4816

European-Finnish (FIN) AF: 0.293 AC: 3098 AN: 10578

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.281 AC: 19119 AN: 67960

Other (OTH) AF: 0.404 AC: 851 AN: 2104

Alfa AF: 0.335 Hom.: 11591

Bravo AF: 0.445

Asia WGS AF: 0.544 AC: 1891 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.58
PhyloP100		0.14
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: rs1157745; hg19: chr7-94941038;