PAH p.Arg176Gly

Variant names:

• chr12-102855316-G-C
• rs199475575
• NM_000277.3:c.526C>G
• PAH p.Arg176Gly

Your query was ambiguous. Multiple possible variants found:

• chr12-102855316-G-C
• chr12-102855314-TCG-ACC
• chr12-102855314-TCG-CCC
• chr12-102855314-TCG-GCC

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5

The NM_000277.3(PAH):c.526C>G (p.Arg176Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R176P: Pathogenic (ClinVar VariationId 102725, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R176= (synonymous): Likely_benign (ClinVar VariationId 2840878, 1 star)

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.975
• Publications: 0 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: Likely_pathogenic. The variant received 6 points.

• PM1: UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 7 pathogenic, 0 benign rare missense variants (OR vs. background: 75.0).; ±8 AA neighbourhood: 35 pathogenic, 0 benign (OR vs. background: 355.0).
• PM2: Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (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.R176P: Pathogenic (ClinVar VariationId 102725, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R176= (synonymous): Likely_benign (ClinVar VariationId 2840878, 1 star)

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>G	p.Arg176Gly	missense	Exon 6 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.526C>G	p.Arg176Gly	missense	Exon 7 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.526C>G	p.Arg176Gly	missense	Exon 6 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.622C>G		non_coding_transcript_exon	Exon 6 of 6
	PAH	ENST00000906695.1		c.526C>G	p.Arg176Gly	missense	Exon 6 of 14	ENSP00000576754.1	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 3 sources Large-scale international reference populations
GnomAD3 genomes					33
GnomAD4 exome					34
GnomAD4 genome					33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	21
AlphaMissense	Benign	-	0.24
BayesDel_addAF	Pathogenic	D	0.23
BayesDel_noAF	Uncertain	-	0.090
CADD	Uncertain	-	24
DANN	Uncertain	-	1.0
DEOGEN2	Pathogenic	D	0.98
Eigen	Benign	-	0.16
Eigen_PC	Benign	-	0.10
FATHMM_MKL	Benign	N	0.41
FuncVEP CTI	Benign	-	0.15
GPN-Star LLR	N/A	-	-6.0
GPN-Star score	N/A	-	6.0
LIST_S2	Benign	T	0.84
M_CAP	Pathogenic	D	0.44
MetaRNN	Pathogenic	D	0.93
MetaSVM	Pathogenic	D	1.1
Mutation Taster	N/A	disease causing	45/55
MutationAssessor	Pathogenic	H	3.9
PhyloP100	Benign	-	0.97
popEVE	Benign	-	-3.2
PrimateAI	Benign	T	0.25
PROVEAN	Pathogenic	D	-5.1
RBP_binding_hub_radar	N/A	-	0.0
RBP_regulation_power_radar	N/A	-	1.1
REVEL	Uncertain	-	0.62
Sift	Uncertain	D	0.0070
Sift4G	Uncertain	D	0.021
Varity_R	N/A	-	0.73
VESM-3B	Benign	-	-10

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.010
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 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.

Other links and lift over

dbSNP: rs199475575;

hg19: chr12-103249094;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar