chr22-46219983-T-C

Variant names:

• chr22-46219983-T-C
• rs1800234
• NM_005036.6:c.680T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005036.6(PPARA):​c.680T>C​(p.Val227Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,614,026 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (127 hom.)
• Consequence: PPARA NM_005036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.771
• Publications: 69 publications found

Genes affected

PPARA (HGNC:9232): (peroxisome proliferator activated receptor alpha) Peroxisome proliferators include hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers; this term arises because they induce an increase in the size and number of peroxisomes. Peroxisomes are subcellular organelles found in plants and animals that contain enzymes for respiration and for cholesterol and lipid metabolism. The action of peroxisome proliferators is thought to be mediated via specific receptors, called PPARs, which belong to the steroid hormone receptor superfamily. PPARs affect the expression of target genes involved in cell proliferation, cell differentiation and in immune and inflammation responses. Three closely related subtypes (alpha, beta/delta, and gamma) have been identified. This gene encodes the subtype PPAR-alpha, which is a nuclear transcription factor. Multiple alternatively spliced transcript variants have been described for this gene, although the full-length nature of only two has been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027141273).
• BP6: Variant 22-46219983-T-C is Benign according to our data. Variant chr22-46219983-T-C is described in ClinVar as Benign. ClinVar VariationId is 770476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00501 (763/152198) while in subpopulation EAS AF = 0.0432 (224/5186). AF 95% confidence interval is 0.0386. There are 18 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 763 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005036.6. 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
	PPARA	NM_005036.6	MANE Select	c.680T>C	p.Val227Ala	missense	Exon 7 of 9	NP_005027.2
	PPARA	NM_001001928.4		c.680T>C	p.Val227Ala	missense	Exon 6 of 8	NP_001001928.1
	PPARA	NM_001001929.3		c.680T>C	p.Val227Ala	missense	Exon 5 of 7	NP_001001929.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARA	ENST00000407236.6	TSL:1 MANE Select	c.680T>C	p.Val227Ala	missense	Exon 7 of 9	ENSP00000385523.1
	PPARA	ENST00000402126.2	TSL:1	c.680T>C	p.Val227Ala	missense	Exon 6 of 8	ENSP00000385246.1
	PPARA	ENST00000493286.1	TSL:1	n.890T>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 760 AN: 152080 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0431

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0112 AC: 2820 AN: 251378 AF XY: 0.00915

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0486

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.0441

Gnomad FIN exome AF: 0.00366

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00349 AC: 5104 AN: 1461828 Hom.: 127 Cov.: 31 AF XY: 0.00327 AC XY: 2381 AN XY: 727222

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.0481 AC: 2152 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26136

East Asian (EAS) AF: 0.0503 AC: 1995 AN: 39696

South Asian (SAS) AF: 0.00268 AC: 231 AN: 86258

European-Finnish (FIN) AF: 0.00403 AC: 215 AN: 53366

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1112010

Other (OTH) AF: 0.00416 AC: 251 AN: 60394

GnomAD4 genome AF: 0.00501 AC: 763 AN: 152198 Hom.: 18 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74414

African (AFR) AF: 0.000650 AC: 27 AN: 41540

American (AMR) AF: 0.0277 AC: 423 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0432 AC: 224 AN: 5186

South Asian (SAS) AF: 0.00312 AC: 15 AN: 4810

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68000

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00332 Hom.: 35

Bravo AF: 0.00811

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00958 AC: 1163

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PPARA-related disorder Benign:1

Jan 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.31
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.77
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.080
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.056
ClinPred		0.0047	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800234; hg19: chr22-46615880; COSMIC: COSV53078755; COSMIC: COSV53078755;