12-102894916-CTC-TTA

Variant names:

• chr12-102894916-CTC-TTA
• NM_000277.3:c.169_171delinsTAA
• PAH p.Glu57Ter

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2

The NM_000277.3(PAH):c.169_171delinsTAA (p.Glu57Ter) variant causes a stop gained, splice region change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 stop_gained, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.42
• 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, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women's Health, G2P
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive 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: Pathogenic. The variant received 10 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 3 of 13) at amino acid 57 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		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_171delinsTAA p.Glu57Ter	stop_gainedsplice_region	Exon 3 of 13	Prot: NP_000268.1
	PAH NM_001354304.2		c.169_171delinsTAA p.Glu57Ter	stop_gainedsplice_region	Exon 4 of 14	Prot: NP_001341233.1

PAH NM_000277.3

MANE Select

HGVSc / HGVSpc.169_171delinsTAAp.Glu57Ter

Exon rankExon 3 of 13

stop_gainedsplice_region

Prot: NP_000268.1

PAH NM_001354304.2

HGVSc / HGVSpc.169_171delinsTAAp.Glu57Ter

Exon rankExon 4 of 14

stop_gainedsplice_region

Prot: NP_001341233.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PAH ENST00000553106.6	MANE Select	c.169_171delinsTAA p.Glu57Ter	stop_gainedsplice_region	Exon 3 of 13	Prot: ENSP00000448059
	PAH ENST00000549111.5	TSL:1	n.265_267delinsTAA	splice_regionnon_coding_transcript_exon	Exon 3 of 6	Prot:
	PAH ENST00000906695.2		c.169_171delinsTAA p.Glu57Ter	stop_gainedsplice_region	Exon 3 of 14	Prot: ENSP00000576754

PAH ENST00000553106.6

MANE Select

HGVSc / HGVSpc.169_171delinsTAAp.Glu57Ter

Exon rankExon 3 of 13

stop_gainedsplice_region

Prot: ENSP00000448059

PAH ENST00000549111.5

TSL:1

HGVSc / HGVSpn.265_267delinsTAA

Exon rankExon 3 of 6

splice_regionnon_coding_transcript_exon

Prot:

PAH ENST00000906695.2

HGVSc / HGVSpc.169_171delinsTAAp.Glu57Ter

Exon rankExon 3 of 14

stop_gainedsplice_region

Prot: ENSP00000576754

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

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.

Other links and lift over

hg19: chr12-103288694;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar