chr12-102894918-C-T

Variant names:

• chr12-102894918-C-T
• rs140945592
• NM_000277.3:c.169G>A
• PAH p.Glu57Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACMG Germline Pathogenicity v2019). PM1PM2_SupportingPP3_Moderate

The NM_000277.3(PAH):c.169G>A (p.Glu57Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000192 (AC=31) in the gnomAD database across 1,611,646 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000141. Variant has been reported in ClinVar as Uncertain Significance (★★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PAH NM_000277.3 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 5.27
• Publications: 2 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

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.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		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: 16 pathogenic, 0 benign (OR vs. background: 165.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000141 — borderline rare for AR gene (base 0.001, raised to 0.00132 by highest known P/LP ClinVar AF 0.00132) — PM2 supporting.
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.

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.169G>A p.Glu57Lys	missensesplice_region	Exon 3 of 13	Prot: NP_000268.1 UniProt:
	PAH NM_001354304.2		c.169G>A p.Glu57Lys	missensesplice_region	Exon 4 of 14	Prot: NP_001341233.1 UniProt:

PAH NM_000277.3

MANE Select

HGVSc / HGVSpc.169G>Ap.Glu57Lys

Exon rankExon 3 of 13

missensesplice_region

Prot: NP_000268.1UniProt: P00439

PAH NM_001354304.2

HGVSc / HGVSpc.169G>Ap.Glu57Lys

Exon rankExon 4 of 14

missensesplice_region

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.169G>A p.Glu57Lys	missensesplice_region	Exon 3 of 13	Prot: ENSP00000448059.1 UniProt:
	PAH ENST00000549111.5	TSL:1	n.265G>A	splice_regionnon_coding_transcript_exon	Exon 3 of 6	Prot:
	PAH ENST00000906695.1		c.169G>A p.Glu57Lys	missensesplice_region	Exon 3 of 14	Prot: ENSP00000576754.1 UniProt:

PAH ENST00000553106.6

TSL:1MANE Select

HGVSc / HGVSpc.169G>Ap.Glu57Lys

Exon rankExon 3 of 13

missensesplice_region

Prot: ENSP00000448059.1UniProt: P00439

PAH ENST00000549111.5

TSL:1

HGVSc / HGVSpn.265G>A

Exon rankExon 3 of 6

splice_regionnon_coding_transcript_exon

Prot:

PAH ENST00000906695.1

HGVSc / HGVSpc.169G>Ap.Glu57Lys

Exon rankExon 3 of 14

missensesplice_region

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:152048	Cov:32
GnomAD2 exomes	AF: 0.0000120	AC:3	Hom:	AN:250312	Cov:
GnomAD4 exome	AF: 0.0000206	AC:30	Hom:0	AN:1459598	Cov:29
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:152048	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000774	AC:2	Hom:0	AN:25828	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000193	2	103362	0.0000108	2	184646

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
-	2	-	Phenylketonuria (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	0.019
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Benign	0.0065
GPN-Star LLR	N/A	-5.6
GPN-Star score	N/A	5.6
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Pathogenic	0.94	D
Mutation Taster	N/A	21/79	disease causing
MutationAssessor	Benign	1.4	L
PhyloP100	Uncertain	5.3
popEVE	Benign	-2.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.51
Sift	Benign	0.32	T
Sift4G	Benign	0.64	T
Varity_R	N/A	0.84
VESM-3B	Benign	-6.9

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
DS_AG_spliceai	Pathogenic	0.64	Position offset: -3
Pangolin (max)	Uncertain	0.26
Pangolin gain	Uncertain	0.26	Position offset: -3
SpliceAI score (max)	Pathogenic	0.64	Details are displayed if max score is > 0.2

Showing 6 of 6 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: rs140945592;

hg19: chr12-103288696;

COSMIC: COSV61017958;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar