Genetic Variant NM_012393.3:c.1862T>C (chr17-8264282-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012393.3(PFAS):c.1862T>C(p.Leu621Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,613,322 control chromosomes in the GnomAD database, including 416,567 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.66 ( 34192 hom., cov: 31)

Exomes 𝑓: 0.72 ( 382375 hom. )

Consequence

PFAS
NM_012393.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0540

Publications

29 publications found

Variant links:

Genes affected

PFAS (HGNC:8863): (phosphoribosylformylglycinamidine synthase) Purines are necessary for many cellular processes, including DNA replication, transcription, and energy metabolism. Ten enzymatic steps are required to synthesize inosine monophosphate (IMP) in the de novo pathway of purine biosynthesis. The enzyme encoded by this gene catalyzes the fourth step of IMP biosynthesis. [provided by RefSeq, Jul 2008]

PFAS links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3859096E-6).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFAS	NM_012393.3 link	c.1862T>C	p.Leu621Pro	missense_variant	Exon 16 of 28	ENST00000314666.11	NP_036525.1	O15067Q6P4B4A8K9T9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFAS	ENST00000314666.11 link	c.1862T>C	p.Leu621Pro	missense_variant	Exon 16 of 28	1	NM_012393.3	ENSP00000313490.6		O15067

Frequencies

GnomAD3 genomes

AF:

0.661

AC:

100299

AN:

151776

Hom.:

34176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.566

Gnomad AMI

AF:

0.677

Gnomad AMR

AF:

0.584

Gnomad ASJ

AF:

0.666

Gnomad EAS

AF:

0.281

Gnomad SAS

AF:

0.553

Gnomad FIN

AF:

0.750

Gnomad MID

AF:

0.595

Gnomad NFE

AF:

0.758

Gnomad OTH

AF:

0.657

GnomAD2 exomes

AF:

0.645

AC:

161836

AN:

251012

AF XY:

0.651

show subpopulations

Gnomad AFR exome

AF:

0.555

Gnomad AMR exome

AF:

0.496

Gnomad ASJ exome

AF:

0.676

Gnomad EAS exome

AF:

0.286

Gnomad FIN exome

AF:

0.755

Gnomad NFE exome

AF:

0.756

Gnomad OTH exome

AF:

0.681

GnomAD4 exome

AF:

0.715

AC:

1045274

AN:

1461428

Hom.:

382375

Cov.:

AF XY:

0.712

AC XY:

517848

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.547

AC:

18300

AN:

33476

American (AMR)

AF:

0.508

AC:

22700

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

17702

AN:

26118

East Asian (EAS)

AF:

0.253

AC:

10030

AN:

39698

South Asian (SAS)

AF:

0.571

AC:

49188

AN:

86198

European-Finnish (FIN)

AF:

0.752

AC:

40163

AN:

53402

Middle Eastern (MID)

AF:

0.602

AC:

3470

AN:

5766

European-Non Finnish (NFE)

AF:

0.758

AC:

842242

AN:

1111692

Other (OTH)

AF:

0.687

AC:

41479

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

15229

30458

45686

60915

76144

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.661

AC:

100347

AN:

151894

Hom.:

34192

Cov.:

AF XY:

0.656

AC XY:

48665

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.566

AC:

23425

AN:

41392

American (AMR)

AF:

0.584

AC:

8906

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.666

AC:

2308

AN:

3466

East Asian (EAS)

AF:

0.280

AC:

1440

AN:

5144

South Asian (SAS)

AF:

0.554

AC:

2665

AN:

4814

European-Finnish (FIN)

AF:

0.750

AC:

7929

AN:

10570

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.758

AC:

51504

AN:

67932

Other (OTH)

AF:

0.654

AC:

1380

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1616

3231

4847

6462

8078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.712

Hom.:

125147

Bravo

AF:

0.642

TwinsUK

AF:

0.769

AC:

2853

ALSPAC

AF:

0.757

AC:

2919

ESP6500AA

AF:

0.567

AC:

2498

ESP6500EA

AF:

0.753

AC:

6480

ExAC

AF:

0.651

AC:

79037

Asia WGS

AF:

0.423

AC:

1478

AN:

3478

EpiCase

AF:

0.733

EpiControl

AF:

0.739

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

3.7

(source)

DANN

Benign

0.061

DEOGEN2

Benign

0.022

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.052

MetaRNN

Benign

0.0000014

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.0

PhyloP100

0.054

PrimateAI

Benign

0.31

PROVEAN

Benign

0.83

REVEL

Benign

0.024

Sift

Benign

0.36

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.066

MPC

0.36

ClinPred

0.0068

GERP RS

1.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.024

gMVP

0.58

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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NM_012393.3:c.1862T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over