12-102855314-TCG-GCC

Variant names:

• chr12-102855314-TCG-GCC
• NM_000277.3:c.526_528delCGAinsGGC
• PAH p.Arg176Gly

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.526_528delCGAinsGGC (p.Arg176Gly) variant causes a missense 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. 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: 32)
• 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.

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 6 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: 7 pathogenic, 0 benign rare missense variants (OR vs. background: 75.0).; ±8 AA neighbourhood: 35 pathogenic, 0 benign (OR vs. background: 355.0).
	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.
	PM5Novel missense at known pathogenic residue		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.526_528delCGAinsGGC p.Arg176Gly	missense	N/A	Prot: NP_000268.1 UniProt:
	PAH NM_001354304.2		c.526_528delCGAinsGGC p.Arg176Gly	missense	N/A	Prot: NP_001341233.1 UniProt:

PAH NM_000277.3

MANE Select

HGVSc / HGVSpc.526_528delCGAinsGGCp.Arg176Gly

Exon rankN/A

missense

Prot: NP_000268.1UniProt: P00439

PAH NM_001354304.2

HGVSc / HGVSpc.526_528delCGAinsGGCp.Arg176Gly

Exon rankN/A

missense

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.526_528delCGAinsGGC p.Arg176Gly	missense	N/A	Prot: ENSP00000448059.1 UniProt:
	PAH ENST00000549111.5	TSL:1	n.622_624delCGAinsGGC	non_coding_transcript_exon	Exon 6 of 6	Prot:
	PAH ENST00000906695.1		c.526_528delCGAinsGGC p.Arg176Gly	missense	N/A	Prot: ENSP00000576754.1 UniProt:

PAH ENST00000553106.6

TSL:1MANE Select

HGVSc / HGVSpc.526_528delCGAinsGGCp.Arg176Gly

Exon rankN/A

missense

Prot: ENSP00000448059.1UniProt: P00439

PAH ENST00000549111.5

TSL:1

HGVSc / HGVSpn.622_624delCGAinsGGC

Exon rankExon 6 of 6

non_coding_transcript_exon

Prot:

PAH ENST00000906695.1

HGVSc / HGVSpc.526_528delCGAinsGGCp.Arg176Gly

Exon rankN/A

missense

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	Benign	0.97

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: chr12-103249092;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar