rs62514954

chr12-102852829-C-Achr12-102852829-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong

The NM_000277.3(PAH):c.828G>T(p.Met276Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M276K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 O:1
• Conservation: PhyloP100: 2.62

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_000277.3 (PAH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 551519
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102852830-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102857.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.828G>T	p.Met276Ile	missense_variant	7/13	ENST00000553106.6
PAH	NM_001354304.2	c.828G>T	p.Met276Ile	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.828G>T	p.Met276Ile	missense_variant	7/13	1	NM_000277.3	P1
PAH	ENST00000307000.7	c.813G>T	p.Met271Ile	missense_variant	8/14	5
PAH	ENST00000549247.6	n.587G>T		non_coding_transcript_exon_variant	1/6	2
PAH	ENST00000635477.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Jan 17, 2021

The c.828G>T (p.Met276Ile) variant in PAH has been reported detected in a control clone from a subject who did not have PKU (PMID: 8364546, 9634518) This variant is absent from gnomAD, 1000G, ESP, and PAGE. Computational evidence is conflicting (Disease causing in MutationTaster, tolerated in SIFT, benign in PolyPhen2). There are 3 other missense changes at this amino acid: M276R (interpretation not provided in ClinVar, ID 102858); M276K (Likely Pathogenic in ClinVar, ID 102857); M276V (Likely Pathogenic in ClinVar, ID 102856). A different codon change leading to the same amino acid change, c.828G>A, has been interpreted as a variant of uncertain significance in ClinVar (ID 551519). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2. -

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	0.70
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.14	B;.
Vest4		0.70
MutPred		0.89		Loss of solvent accessibility (P = 0.0387);.;
MVP		0.96
MPC		0.042
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62514954; hg19: chr12-103246607;