17-8264282-T-C

Variant names:

• chr17-8264282-T-C
• rs11078738
• NM_012393.3:c.1862T>C

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0540
• Publications: 29 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=1.3859096E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012393.3. 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
	PFAS	NM_012393.3	MANE Select	c.1862T>C	p.Leu621Pro	missense	Exon 16 of 28	NP_036525.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFAS	ENST00000314666.11	TSL:1 MANE Select	c.1862T>C	p.Leu621Pro	missense	Exon 16 of 28	ENSP00000313490.6
	PFAS	ENST00000580356.5	TSL:2	n.*1392T>C		non_coding_transcript_exon	Exon 14 of 26	ENSP00000464671.1
	PFAS	ENST00000581288.1	TSL:4	n.300T>C		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100299 AN: 151776 Hom.: 34176 Cov.: 31

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

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.: 52 AF XY: 0.712 AC XY: 517848 AN XY: 727032

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

GnomAD4 genome AF: 0.661 AC: 100347 AN: 151894 Hom.: 34192 Cov.: 31 AF XY: 0.656 AC XY: 48665 AN XY: 74222

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.7
DANN	Benign	0.061
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.052	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.0	N
PhyloP100		0.054
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.024
Sift	Benign	0.36	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.066
MPC		0.36
ClinPred		0.0068	T
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)

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: rs11078738; hg19: chr17-8167600; COSMIC: COSV58980417; COSMIC: COSV58980417;