Genetic Variant PAH:p.Glu57Lys (chr12-102894916-CTC-TTT) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM1PM2

The NM_000277.3(PAH):c.169_171delGAGinsAAA (p.Glu57Lys) variant causes a missense, splice region change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E57K: Uncertain_significance (ClinVar VariationId 92737, 3 stars) 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: not found (cov: 32)

Consequence

PAH
NM_000277.3 missense, splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.42

Publications

0 publications found

Variant links:

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

PAH links:

LOC124902999 (HGNC:):

LOC124902999 links:

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new If you want to explore the variant's impact on the transcript NM_000277.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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 4 points.

Show applied only (2)

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		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.

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.169_171delGAGinsAAA p.Glu57Lys	missensesplice_region	N/A	Prot: NP_000268.1 UniProt: P00439
	PAH NM_001354304.2		c.169_171delGAGinsAAA p.Glu57Lys	missensesplice_region	N/A	Prot: NP_001341233.1 UniProt: P00439

PAH NM_000277.3

MANE Select

HGVSc / HGVSpc.169_171delGAGinsAAAp.Glu57Lys

Exon rankN/A

missensesplice_region

Prot: NP_000268.1UniProt: P00439

PAH NM_001354304.2

HGVSc / HGVSpc.169_171delGAGinsAAAp.Glu57Lys

Exon rankN/A

missensesplice_region

Prot: NP_001341233.1UniProt: P00439

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
PAH ENST00000553106.6	TSL:1MANE Select	c.169_171delGAGinsAAA p.Glu57Lys	missensesplice_region	N/A	Prot: ENSP00000448059.1 UniProt: P00439
PAH ENST00000549111.5	TSL:1	n.265_267delGAGinsAAA	splice_regionnon_coding_transcript_exon	Exon 3 of 6	Prot:
PAH ENST00000906695.1		c.169_171delGAGinsAAA p.Glu57Lys	missensesplice_region	N/A	Prot: ENSP00000576754.1 UniProt: A0ACI8RXH2

PAH ENST00000553106.6

TSL:1MANE Select

HGVSc / HGVSpc.169_171delGAGinsAAAp.Glu57Lys

Exon rankN/A

missensesplice_region

Prot: ENSP00000448059.1UniProt: P00439

PAH ENST00000549111.5

TSL:1

HGVSc / HGVSpn.265_267delGAGinsAAA

Exon rankExon 3 of 6

splice_regionnon_coding_transcript_exon

Prot:

PAH ENST00000906695.1

HGVSc / HGVSpc.169_171delGAGinsAAAp.Glu57Lys

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	5.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence