rs199475605

Variant names:

• chr12-102877501-CTGAT-C
• rs199475605
• NM_000277.3:c.398_401delATCA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM3_Strong PM2 PP4_Moderate PVS1

This summary comes from the ClinGen Evidence Repository: This c.398_401del (p.Asn133fs) variant in PAH was detected with pathogenic and likely pathogenic variants in multiple patients with classic PKU and one with mild hyperphenylalaninemia (PMID:22513348, 22526846, 8659548, 22917871, 26666653). This variant was absent in population databases. This is a frameshift variant in exon 4 of 13 predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Strong, PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229531/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 9.18
• 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):

• phenylketonuria

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

LOC124902999 (HGNC:):

ACMG classification

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• 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.

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.398_401delATCA	p.Asn133ArgfsTer61	frameshift	Exon 4 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.398_401delATCA	p.Asn133ArgfsTer61	frameshift	Exon 5 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.398_401delATCA	p.Asn133ArgfsTer61	frameshift	Exon 4 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.494_497delATCA		non_coding_transcript_exon	Exon 4 of 6
	PAH	ENST00000906695.1		c.398_401delATCA	p.Asn133ArgfsTer61	frameshift	Exon 4 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Phenylketonuria (5)
1	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199475605; hg19: chr12-103271279;