12-102894893-A-T

Position:

• chr12-102894893-A-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.194T>A (p.Ile65Asn) variant was identified in a patient with classic PKU. BH4 deficiency was ruled out. (PMID:9521426). It was detected in trans with known pathogenic mutation c.143T>C (p.L48S). It has an extremely low frequency in PAGE (0.00026); and is absent from ExAC, 1000 Genomes, gnomAD. Multiple lines of computational evidence support a deleterious effect (SIFT, Polyphen-2, MutationTaster; REVEL=0.957). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229479/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH ENST00000553106.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 8.30

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]

LOC124902999 (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.194T>A	p.Ile65Asn	missense_variant	3/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.863-9805A>T		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.194T>A	p.Ile65Asn	missense_variant	4/14		NP_001341233.1
PAH	XM_017019370.2	c.194T>A	p.Ile65Asn	missense_variant	3/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.194T>A	p.Ile65Asn	missense_variant	3/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Dec 09, 2018

The c.194T>A (p.Ile65Asn) variant was identified in a patient with classic PKU. BH4 deficiency was ruled out. (PMID: 9521426). It was detected in trans with known pathogenic mutation c.143T>C (p.L48S). It has an extremely low frequency in PAGE (0.00026); and is absent from ExAC, 1000 Genomes, gnomAD. Multiple lines of computational evidence support a deleterious effect (SIFT, Polyphen-2, MutationTaster; REVEL=0.957). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PP3. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.6	H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.3	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.96		Gain of disorder (P = 0.0063);.;Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);
MVP		0.99
MPC		0.29
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.99
gMVP		0.96

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: rs75193786; hg19: chr12-103288671;