12-102894883-T-A

Variant names:

• chr12-102894883-T-A
• rs76394784
• NM_000277.3:c.204A>T
• PAH p.Arg68Ser

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 19 classification points (ACMG Germline Pathogenicity v2019): 19P and 0B. PS3PM1PM2_SupportingPM5PP3_ModeratePP5_Very_Strong

The NM_000277.3(PAH):c.204A>T (p.Arg68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000737 (AC=119) in the gnomAD database across 1,613,714 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00017. 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: "SCV000629187: Experimental studies have shown that this missense change affects PAH function (PMID:21953985).". A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R68G: Pathogenic (ClinVar VariationId 102627, 3 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R68= (synonymous): Likely_benign (ClinVar VariationId 2810941, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13 O:1
• Conservation: PhyloP100: 1.03
• Publications: 35 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Myriad Women's Health, ClinGen
• 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

LOC124902999 (HGNC:):

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 19 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000629187: Experimental studies have shown that this missense change affects PAH function (PMID: 21953985).
• PM1: UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 67 pathogenic, 0 benign rare missense variants (OR vs. background: 675.0).; ±8 AA neighbourhood: 23 pathogenic, 0 benign (OR vs. background: 235.0).
• PM2: Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.00017 — borderline rare for AR gene (base 0.001, raised to 0.00132 by highest known P/LP ClinVar AF 0.00132) — PM2 supporting.
• 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.R68G: Pathogenic (ClinVar VariationId 102627, 3 stars); Other variants at the same amino acid residue (not pathogenic): p.R68= (synonymous): Likely_benign (ClinVar VariationId 2810941, 1 star)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• 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 (13/13 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.204A>T	p.Arg68Ser	missense	Exon 3 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.204A>T	p.Arg68Ser	missense	Exon 4 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.204A>T	p.Arg68Ser	missense	Exon 3 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.300A>T		non_coding_transcript_exon	Exon 3 of 6
	PAH	ENST00000906695.1		c.204A>T	p.Arg68Ser	missense	Exon 3 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000477 AC: 12 AN: 251332 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1461672 Hom.: 0 Cov.: 30 AF XY: 0.0000688 AC XY: 50 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1111876

Other (OTH) AF: 0.0000497 AC: 3 AN: 60378

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74258

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.000393 AC: 6 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

Local populations

ABraOM SABE-WGS-1171 AF: 0.000427 AC: 1 AN: 2342 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Phenylketonuria (8)
4	-	-	not provided (5)
1	-	-	PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		1.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.90
Sift	Benign	0.036	D
Sift4G	Uncertain	0.024	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76394784;

hg19: chr12-103288661;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar