12-102855255-G-T

Position:

• chr12-102855255-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM3 PP4 PM2_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.587C>A (p.Ser196Tyr) variant in PAH has been reported in one individual with mild hyperphenylalanemia, without exclusion of BH4 deficiency (PMID:23792259). In this individual, c.587C>A occurred de novo on the paternal allele, with confirmation of paternity. c.842+3G>C was present on the maternal allele (classified as likely pathogenic by PAH VCEP, Variation ID: 102871). In-vitro studies show 21% enzyme activity (PMID:27620137). This variant is present below the 0.0002 allele frequency threshold for PAH in population databases. Multiple lines of computational evidence yield conflicting predictions regarding the effect of this variant (REVEL=0.542). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020823/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 3.25

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 Uncertain_significance. Variant got 5 ACMG points.

• PS3: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.587C>A	p.Ser196Tyr	missense_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.587C>A	p.Ser196Tyr	missense_variant	7/14		NP_001341233.1
PAH	XM_017019370.2	c.587C>A	p.Ser196Tyr	missense_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.587C>A	p.Ser196Tyr	missense_variant	6/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.683C>A		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.572C>A	p.Ser191Tyr	missense_variant	7/14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.*24C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251342 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 28, 2018	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Mar 08, 2024	The c.587C>A (p.Ser196Tyr) variant in PAH has been reported in one individual with mild hyperphenylalanemia, without exclusion of BH4 deficiency (PMID: 23792259). In this individual, c.587C>A occurred de novo on the paternal allele, with confirmation of paternity. c.842+3G>C was present on the maternal allele (classified as likely pathogenic by PAH VCEP, Variation ID: 102871). In-vitro studies show 21% enzyme activity (PMID: 27620137). This variant is present below the 0.0002 allele frequency threshold for PAH in population databases. Multiple lines of computational evidence yield conflicting predictions regarding the effect of this variant (REVEL=0.542). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4, PM2_supporting, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Benign	-0.043
Eigen_PC	Benign	0.0049
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.064	B;.
Vest4		0.56
MutPred		0.57		Gain of methylation at K192 (P = 0.0505);.;
MVP		0.96
MPC		0.068
ClinPred		0.58	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.82

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: rs865899394; hg19: chr12-103249033;