rs542645236

chr12-102894767-T-Cchr12-102894767-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_000277.3(PAH):c.320A>G(p.His107Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H107P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.13

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr12-102894767-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1523410.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 12-102894767-T-C is Pathogenic according to our data. Variant chr12-102894767-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 225134.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102894767-T-C is described in Lovd as [Pathogenic]. Variant chr12-102894767-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.30792373).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.320A>G	p.His107Arg	missense_variant	3/13	ENST00000553106.6
LOC124902999	XR_007063428.1	n.863-9931T>C		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.320A>G	p.His107Arg	missense_variant	4/14
PAH	XM_017019370.2	c.320A>G	p.His107Arg	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.320A>G	p.His107Arg	missense_variant	3/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251446 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000850 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 107 of the PAH protein (p.His107Arg). This variant is present in population databases (rs542645236, gnomAD 0.006%). This missense change has been observed in individual(s) with PAH-related disease (PMID: 21307867, 25456745, 26600521, 29390883, 30050108). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225134). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital	Oct 01, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 19, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 09, 2020	This c.320A>G (p.His107Arg) variant in PAH was reported in 22 patients with PAH deficiency (>120 uMol/L Phe), detected in trans in 16 patients with pathogenic variants p.Arg111*, p.Arg400Thr, p.Val399=, p.Val399=, p.Arg241Cys, p.Arg241Cys, p.Arg413Pro, p.Gly257Val, p.His107Arg, p.Arg243Gln, p.His220Pro, p.Arg176*, p.Arg243Gln, p.Arg243Gln, p.Val230Ile, p.Ile65Thr (PMID: 28982351). Computational evidence for this variant is conflicting; predicted to be tolerated (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is present in European (Non-Finnish) populations at extremely low frequencies in gnomAD (MAF=0.00002), ExAC (MAF=0.00001), and 1000 Genomes (MAF=0.00099). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_very-strong, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 13, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.29	T;T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.071
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.78	N;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.46	N;N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.41	T;T;T;T
Sift4G	Benign	0.54	T;T;T;.
Polyphen		0.037	B;.;.;.
Vest4		0.93
MutPred		0.29		Gain of MoRF binding (P = 0.0179);.;Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);
MVP		0.96
MPC		0.034
ClinPred		0.33	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.84

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: rs542645236; hg19: chr12-103288545;