17-8253992-C-T

Variant names:

• chr17-8253992-C-T
• rs9891699
• NM_012393.3:c.55C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012393.3(PFAS):​c.55C>T​(p.Pro19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 1,613,700 control chromosomes in the GnomAD database, including 485,964 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 0.70 (39097 hom., cov: 31)
  • Exomes 𝑓: 0.78 (446867 hom.)
• Consequence: PFAS NM_012393.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.238
• Publications: 39 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=6.0514793E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFAS	NM_012393.3	c.55C>T	p.Pro19Ser	missense_variant	Exon 2 of 28	ENST00000314666.11	NP_036525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFAS	ENST00000314666.11	c.55C>T	p.Pro19Ser	missense_variant	Exon 2 of 28	1	NM_012393.3	ENSP00000313490.6

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106938 AN: 151912 Hom.: 39066 Cov.: 31

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.699

GnomAD2 exomes AF: 0.748 AC: 187998 AN: 251288 AF XY: 0.748

Gnomad AFR exome AF: 0.492

Gnomad AMR exome AF: 0.802

Gnomad ASJ exome AF: 0.709

Gnomad EAS exome AF: 0.551

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.802

Gnomad OTH exome AF: 0.765

GnomAD4 exome AF: 0.779 AC: 1138210 AN: 1461668 Hom.: 446867 Cov.: 52 AF XY: 0.776 AC XY: 564575 AN XY: 727142

African (AFR) AF: 0.492 AC: 16459 AN: 33474

American (AMR) AF: 0.795 AC: 35546 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 18569 AN: 26128

East Asian (EAS) AF: 0.589 AC: 23382 AN: 39692

South Asian (SAS) AF: 0.680 AC: 58653 AN: 86244

European-Finnish (FIN) AF: 0.849 AC: 45357 AN: 53396

Middle Eastern (MID) AF: 0.692 AC: 3989 AN: 5766

European-Non Finnish (NFE) AF: 0.801 AC: 891154 AN: 1111864

Other (OTH) AF: 0.747 AC: 45101 AN: 60388

GnomAD4 genome AF: 0.704 AC: 107012 AN: 152032 Hom.: 39097 Cov.: 31 AF XY: 0.706 AC XY: 52469 AN XY: 74338

African (AFR) AF: 0.505 AC: 20920 AN: 41424

American (AMR) AF: 0.750 AC: 11447 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2396 AN: 3472

East Asian (EAS) AF: 0.564 AC: 2913 AN: 5166

South Asian (SAS) AF: 0.671 AC: 3230 AN: 4814

European-Finnish (FIN) AF: 0.856 AC: 9067 AN: 10594

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54739 AN: 67982

Other (OTH) AF: 0.696 AC: 1464 AN: 2102

Alfa AF: 0.759 Hom.: 153501

Bravo AF: 0.687

TwinsUK AF: 0.810 AC: 3003

ALSPAC AF: 0.803 AC: 3093

ESP6500AA AF: 0.507 AC: 2234

ESP6500EA AF: 0.803 AC: 6904

ExAC AF: 0.743 AC: 90207

Asia WGS AF: 0.620 AC: 2161 AN: 3478

EpiCase AF: 0.783

EpiControl AF: 0.787

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.46
DANN	Benign	0.85
DEOGEN2	Benign	0.0027	.;T;T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.061	T;T;T;T;T
MetaRNN	Benign	6.1e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	.;.;N;.;.
PhyloP100		-0.24
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.6	.;.;N;.;.
REVEL	Benign	0.020
Sift	Benign	0.87	.;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;.;B;.;.
Vest4		0.025, 0.027
MPC		0.23
ClinPred		0.00071	T
GERP RS		-1.2
PromoterAI		0.24	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.27
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: rs9891699; hg19: chr17-8157310; COSMIC: COSV58979199;