rs199475604

Positions:

• chr12-102855319-G-A
• chr12-102855319-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3 PP3 PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: The c.523C>T (p.Pro175Ser) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded) in trans with pathogenic variant p.R413P (PP4_Moderate, PM3; PMID:26322415). This variant is absent in population databases (PM2). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020810/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.523C>T	p.Pro175Ser	missense_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.523C>T	p.Pro175Ser	missense_variant	7/14		NP_001341233.1
PAH	XM_017019370.2	c.523C>T	p.Pro175Ser	missense_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.523C>T	p.Pro175Ser	missense_variant	6/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.619C>T		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.508C>T	p.Pro170Ser	missense_variant	7/14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.544C>T		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Apr 08, 2019	The c.523C>T (p.Pro175Ser) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded) in trans with pathogenic variant p.R413P (PP4_Moderate, PM3; PMID: 26322415). This variant is absent in population databases (PM2). Computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 07, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.5	H;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.92		Loss of stability (P = 0.0885);.;
MVP		0.99
MPC		0.24
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs199475604; hg19: chr12-103249097;