rs9891699

Positions:

• chr17-8253992-C-G
• chr17-8253992-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012393.3(PFAS):​c.55C>G​(p.Pro19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P19S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PFAS NM_012393.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.238

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021454334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFAS	NM_012393.3	c.55C>G	p.Pro19Ala	missense_variant	2/28	ENST00000314666.11	NP_036525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFAS	ENST00000314666.11	c.55C>G	p.Pro19Ala	missense_variant	2/28	1	NM_012393.3	ENSP00000313490.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.19
DANN	Benign	0.72
DEOGEN2	Benign	0.0028	.;T;T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.099	T;T;T;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.021	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.81	.;.;N;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.76	.;.;N;.;.
REVEL	Benign	0.044
Sift	Benign	0.66	.;.;T;.;.
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.0	.;.;B;.;.
Vest4		0.084, 0.11
MutPred		0.32		Gain of catalytic residue at P19 (P = 0.0329);Gain of catalytic residue at P19 (P = 0.0329);Gain of catalytic residue at P19 (P = 0.0329);Gain of catalytic residue at P19 (P = 0.0329);Gain of catalytic residue at P19 (P = 0.0329);
MVP		0.52
MPC		0.22
ClinPred		0.054	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.012
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs9891699; hg19: chr17-8157310;