12-102851756-AGG-TCT

Variant names:

• chr12-102851756-A-T
• rs772249197
• NM_000277.3:c.843T>A
• PAH p.Pro281Pro

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP4 PM3_Supporting PM2 BP7

This summary comes from the ClinGen Evidence Repository: This c.843T>A (p.Pro281Pro) variant in PAH was detected with the pathogenic variant c.168+5G>C in a patient with PKU (PMID:26413448). This variant was absent in population databases. This is a synonymous variant which is not predicted to have a splice-altering consequence. In summary, this variant meets criteria to be classified as a variant of unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: BP7, PM3_Supporting, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA481331323/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001607
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 0.0950
• Publications: 1 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):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women's Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.843T>A	p.Pro281Pro	splice_region synonymous	Exon 8 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.843T>A	p.Pro281Pro	splice_region synonymous	Exon 9 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.843T>A	p.Pro281Pro	splice_region synonymous	Exon 8 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.942T>A	p.Asn314Lys	missense splice_region	Exon 9 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.843T>A	p.Pro281Pro	splice_region synonymous	Exon 8 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Phenylketonuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.66
PhyloP100		0.095
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.060		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: rs772249197;

hg19: chr12-103245534;