NM_000277.3:c.526C>T

Variant names:

• chr12-102855316-G-A
• rs199475575
• NM_000277.3:c.526C>T
• PAH p.Arg176*

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 18 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Very_Strong

The NM_000277.3(PAH):c.526C>T (p.Arg176*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000112 (AC=18) in the gnomAD database across 1,613,890 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000192. In-silico predictor (BayesDel (noAF)) 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 (★★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:18 O:1
• Conservation: PhyloP100: 0.975
• Publications: 9 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.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 6 of 13) at amino acid 176 of 452, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000192 — very rare for AR gene (base 0.001, raised to 0.00132 by highest known P/LP ClinVar AF 0.00132) — PM2 moderate.
	PP5Reputable source reports pathogenic		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 (18/18 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.526C>T p.Arg176*	stop_gained	Exon 6 of 13	Prot: NP_000268.1 UniProt:
	PAH NM_001354304.2		c.526C>T p.Arg176*	stop_gained	Exon 7 of 14	Prot: NP_001341233.1 UniProt:

PAH NM_000277.3

MANE Select

HGVSc / HGVSpc.526C>Tp.Arg176*

Exon rankExon 6 of 13

stop_gained

Prot: NP_000268.1UniProt: P00439

PAH NM_001354304.2

HGVSc / HGVSpc.526C>Tp.Arg176*

Exon rankExon 7 of 14

stop_gained

Prot: NP_001341233.1UniProt: P00439

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PAH ENST00000553106.6	TSL:1MANE Select	c.526C>T p.Arg176*	stop_gained	Exon 6 of 13	Prot: ENSP00000448059.1 UniProt:
	PAH ENST00000549111.5	TSL:1	n.622C>T	non_coding_transcript_exon	Exon 6 of 6	Prot:
	PAH ENST00000906695.1		c.526C>T p.Arg176*	stop_gained	Exon 6 of 14	Prot: ENSP00000576754.1 UniProt:

PAH ENST00000553106.6

TSL:1MANE Select

HGVSc / HGVSpc.526C>Tp.Arg176*

Exon rankExon 6 of 13

stop_gained

Prot: ENSP00000448059.1UniProt: P00439

PAH ENST00000549111.5

TSL:1

HGVSc / HGVSpn.622C>T

Exon rankExon 6 of 6

non_coding_transcript_exon

Prot:

PAH ENST00000906695.1

HGVSc / HGVSpc.526C>Tp.Arg176*

Exon rankExon 6 of 14

stop_gained

Prot: ENSP00000576754.1UniProt: A0ACI8RXH2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000329	AC:5	Hom:0	AN:152074	Cov:33
GnomAD2 exomes	AF: 0.0000119	AC:3	Hom:	AN:251136	Cov:
GnomAD4 exome	AF: 0.00000889	AC:13	Hom:0	AN:1461816	Cov:34
GnomAD4 genome	AF: 0.0000329	AC:5	Hom:0	AN:152074	Cov:33
TOPMed (Bravo)	AF: 0.0000378	AC:10	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000893	AC:2	Hom:0	AN:223938	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000240	AC:3	Hom:0	AN:122792	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000443	5	112964	0.0000210	4	190206

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
14	-	-	Phenylketonuria (14)
4	-	-	not provided (5)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	38
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.34	N
GPN-Star LLR	N/A	-7.1
GPN-Star score	N/A	7.1
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	0.97

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.17
Pangolin loss	Benign	0.17	Position offset: 16
SpliceAI score (max)	Benign	0.13	Details are displayed if max score is > 0.2

Showing 3 of 3 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs199475575;

hg19: chr12-103249094;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar