dbSNP rs118092776: PAH:p.Arg53Pro (chr12-102912801-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000277.3(PAH):c.158G>C(p.Arg53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.51

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a helix (size 10) in uniprot entity PH4H_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) 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 chr12-102912801-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 3 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.158G>C	p.Arg53Pro	missense_variant	Exon 2 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456586

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;D

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;.

Polyphen

0.70

P;.;.;.

Vest4

0.85

MutPred

0.69

Gain of ubiquitination at K50 (P = 0.1317);.;Gain of ubiquitination at K50 (P = 0.1317);Gain of ubiquitination at K50 (P = 0.1317);

MVP

0.99

MPC

0.096

ClinPred

0.99

GERP RS

5.5

Varity_R

0.97

gMVP

0.93

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over