rs5030847

Variant names:

• chr12-102852903-G-A
• rs5030847
• NM_000277.3:c.754C>T
• PAH p.Arg252Trp

Your query was ambiguous. Multiple possible variants found:

• chr12-102852903-G-A
• chr12-102852903-G-C
• chr12-102852903-G-T

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 22 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000277.3(PAH):c.754C>T (p.Arg252Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000428 (AC=69) in the gnomAD database across 1,613,988 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000061. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000629214: Experimental studies have shown that this missense change affects PAH function (PMID:12655546, 25596310)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R252G: Pathogenic (ClinVar VariationId 102823, 3 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R252= (synonymous): Likely_benign (ClinVar VariationId 3633095, 1 star); p.R252= (synonymous): Likely_benign (ClinVar VariationId 1619178, 1 star); p.R252= (synonymous): Likely_benign (ClinVar VariationId 2884221, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Phenylketonuria (pku); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17 O:1
• Conservation: PhyloP100: 3.29
• Publications: 91 publications found

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH Gene-Disease associations (from GenCC):

• classic phenylketonuria

  Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women's Health
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 22 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000629214: Experimental studies have shown that this missense change affects PAH function (PMID: 12655546, 25596310).; SCV000852089: "PS3: 1% residual activity (PMID:25596310; PMID:17935162)"; SCV000239071: Published functional studies demonstrates R252W results in no detectable PAH activity (Pey et al., 2003; Danecka et al., 2015)
• PM1: UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 11 pathogenic, 0 benign rare missense variants (OR vs. background: 115.0).; ±8 AA neighbourhood: 24 pathogenic, 0 benign (OR vs. background: 245.0).
• PM2: Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000061 — very rare for AR gene (base 0.001, raised to 0.00132 by highest known P/LP ClinVar AF 0.00132) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R252G: Pathogenic (ClinVar VariationId 102823, 3 stars); Other variants at the same amino acid residue (not pathogenic): p.R252= (synonymous): Likely_benign (ClinVar VariationId 3633095, 1 star); p.R252= (synonymous): Likely_benign (ClinVar VariationId 1619178, 1 star); p.R252= (synonymous): Likely_benign (ClinVar VariationId 2884221, 1 star)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
• PP5: ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (17/17 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.754C>T	p.Arg252Trp	missense	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.754C>T	p.Arg252Trp	missense	Exon 8 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.754C>T	p.Arg252Trp	missense	Exon 7 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.754C>T	p.Arg252Trp	missense	Exon 7 of 14	ENSP00000576754.1	A0ACI8RXH2
	PAH	ENST00000906692.1		c.754C>T	p.Arg252Trp	missense	Exon 7 of 13	ENSP00000576751.1	A0ACI8S8A6

Frequencies

GnomAD3 genomes AF: 0.0000458 AC: 8 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000122

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000305 AC: 7 AN: 251272 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000610

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000458

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 61 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.0000458 AC XY: 33 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000153 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39696

South Asian (SAS) AF: 0.0000153 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000458 AC: 49 AN: 1111976

Other (OTH) AF: 0.0000610 AC: 4 AN: 60392

GnomAD4 genome AF: 0.0000458 AC: 8 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000458 AC XY: 3 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000122 AC: 8 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000610 Hom.: 0

Bravo AF: 0.0000610

EpiCase AF: 0.000107

EpiControl AF: 0.0000610

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.000244 AC: 30 AN: 122796

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Phenylketonuria (11)
4	-	-	not provided (5)
1	-	-	Pulmonary hypertension, primary, 1 (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		3.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
PromoterAI		-0.050	Neutral
Varity_R		0.98
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5030847;

hg19: chr12-103246681;

COSMIC: COSV61019811;

COSMIC: COSV61019811;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar